|
|
Next Article 
Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 1-14
REVIEW ARTICLE
Src-Related Protein Tyrosine Kinases in Hematopoiesis
By
Seth J. Corey and
Steven M. Anderson
From the Departments of Pediatrics and Pharmacology, University of
Pittsburgh School of Medicine, Pittsburgh, PA; and the Department of
Pathology and Program in Molecular Biology, University of Colorado
Health Sciences Center, Denver.
 |
HEMATOPOIESIS DEPENDS ON GROWTH FACTOR RECEPTOR-MEDIATED TYROSINE
KINASE SIGNALING |
THE PROLIFERATION and
differentiation of blood cell progenitors and precursors are tightly
regulated by approximately a dozen different growth factors, which act
primarily on hematopoietic cells.1 In addition, growth
factors that stimulate a wider variety of cell types, such as
insulin-like growth factor 1, are also able to stimulate the
proliferation of hematopoietic progenitor cells.2 Both
types of growth factors activate receptor-mediated tyrosine kinase
signaling pathways. Acting as extracellular signals, hematopoietic
growth factors bind to cell-surface receptors and induce a rapid
increase in tyrosine phosphorylated cellular proteins. Tyrosine
phosphorylation of growth factor receptors and cytoplasmic signaling
molecules then serves to amplify the intracellular signal and activate
a diverse number of intracellular signaling pathways. These signaling
pathways suppress apoptosis and induce the transcription of genes
required for mitogenesis. Many of the same signaling molecules are also
activated by growth factors that stimulate terminal differentiation,
rather than proliferation, of precursor cells.
The receptors for three well-established hematopoietic growth factors,
macrophage colony-stimulating factor (M-CSF), stem cell factor (SCF),
and the Flt-3 ligand, are transmembrane tyrosine kinases in which the
cytoplasmic domain of these receptors encodes a tyrosine
kinase.3-8 Ligand binding leads to receptor dimerization and immediate activation of the receptor tyrosine kinase domain. In
contrast, the receptors for the majority of hematopoietic growth factors, including granulocyte CSF (G-CSF), GM-CSF, erythropoietin (Epo), thrombopoietin (Tpo), interleukin-2 (IL-2), IL-3, IL-4, IL-5,
IL-6, IL-7, IL-9, IL-11, IL-13, and IL-15, do not encode a tyrosine
kinase catalytic domain. This latter group of receptors are all members
of the cytokine receptor superfamily.9,10 Cytokine
receptors share several structural motifs in both the extracellular
ligand binding domain and their cytoplasmic tails. A series of four
conserved cysteine residues and the WSXWS motif (Trp-Ser-X-Trp-Ser,
where X is any amino acid) are both present in the extracellular ligand
binding domain of all cytokine receptors. Other highly conserved motifs
found in the juxtamembrane region of the cytoplasmic tail of cytokine
receptors are referred to as the box 1 and box 2 motifs.10,11 Excellent reviews describing the structural
features of cytokine receptor family members have recently been
presented.10,11
The molecular cloning of multiple cytokine receptors a decade ago
showed that none of these receptors encoded a protein tyrosine kinase,
despite the fact that stimulation of cells with various cytokines
resulted in a rapid increase in tyrosine-phosphorylated proteins. This
observation provided the stimulus to identify the tyrosine kinase(s)
activated by these receptors. The structural features of cytokine
receptors, however, did not provide any clues as which tyrosine kinases
might be activated or to the mechanism(s) by which these kinases might
be activated. Studies conducted with a variety of cytokine receptors
have provided evidence that the binding of ligands to cytokine
receptors is able to activate multiple tyrosine kinases including
members of the Janus family kinases,12-16 the Src family of
kinases,17-25 and, more recently, members of the Tec family
of tyrosine kinases.26,27 For the last 5 years the majority
of research on cytokine receptor signaling has focused on the Janus
family of tyrosine kinases, because one or more Janus kinase family
members have been observed to be activated by every cytokine receptor
identified to date. Furthermore, genetic evidence supports a role for
Janus kinases in promoting cytokine-induced differentiation of
hematopoietic cells. A group of patients with severe molecular defects
in Jak3 have pronounced B- and T-cell deficiencies.28,29
Myeloid cells derived from fetal liver cells of Jak2-deficient mice
failed to differentiate in response to IL-3, Epo, or TPO. However,
these cells differentiated normally in response to G-CSF or M-CSF.
Myeloid cells derived from Jak1-deficient mice responded to GM-CSF,
G-CSF, IL-5, and IL-3.30-32 These data suggest unique roles
for Jak1, Jak2, and Jak3.
Regardless of receptor type, the activation of kinases and the
phosphorylation of substrates drive proliferation and differentiation. A common set of downstream targets is phosphorylated by receptors that
induce proliferation or differentiation (Fig
1). We hypothesize that cytokine-stimulated
proliferation is dependent on the activation of Jak and Src-family of
tyrosine kinases. This review will discuss the evidence that Src-like
kinases are required for myeloid hematopoietic cell signaling,
highlight those substrates that are activated/phosphorylated in an
Src-like dependent manner, and describe potential mechanism(s) by which
these kinases are regulated by cytokine receptors. The critical role of
Src-related kinases in the development of T-cell and B-cell lymphocytes
and activation signaling of the multimeric immune receptors (T-cell
receptor, B-cell receptor, and the high-affinity IgE receptor) have
been well reviewed.33-38
View larger version (34K):
[in this window]
[in a new window]
| Fig 1.
Similarities in signaling between a hematopoietic
receptor tyrosine kinase and a hematopoietic cytokine receptor. The
receptors for M-CSF (CSF-1) and G-CSF serve as models for a
hematopoietic receptor tyrosine kinase and a hematopoietic receptor
without intrinsic tyrosine kinase activity. In both cases, upon
receptor engagement, the receptor dimerizes and becomes tyrosine
phosphorylated. The phosphotyrosine residues serve as specific docking
sites for SH2 containing signal transduction molecules, such as Src, PI
3-kinase, Grb2, and STAT. The same pathways involving Cbl-PI
3-Kinase-Akt kinase-Akt or Shc-Grb2-Sos-Ras-Raf-MapKK (Map Kinase
Kinase)-MapK may be activated by both types of receptors via the
receptor and Src. Mutagenesis studies show that the loss of Y559 in the
M-CSF receptor and loss of box 1 and box 2 in the G-CSF receptor lead
to the loss of cytokine-induced mitogenesis.
|
|
| |
THE Src FAMILY OF TYROSINE KINASES |
The v-Src oncogene is derived from the Src cellular proto-oncogene
(frequently identified as c-Src). Seven additional related genes have
been identified either by cloning of related cDNAs or by identification
of related viral oncogenes. The members of the Src kinase family
include: Src, Yes, Fgr, Fyn, Lck, Lyn, Blk, and Hck (Table
1). Some Src family members are expressed
in a wide variety of tissues, while others show a more restricted
pattern of expression. For example, Blk, Hck, Fgr, Lck, and Lyn are
each expressed primarily in a narrow range of hematopoietic cells (see below). In addition, several Src family members exist in multiple isoforms formed by either alternative splicing39-43 or, in
the case of Hck, by the use of an alternative start
codon.44 Adding to the complexity of Src kinase expression
is the fact that these different isoforms can also show differences in
tissue expression; that is, different forms of Fyn are expressed in T
lymphocytes and the brain.39,40 Although three Src kinases,
Src, Yes, and Fgr, were discovered in naturally occurring oncogenic
retroviruses, the introduction of specific point mutations can lead to
the oncogenic activation of all members of the Src kinase family. The
ability of specific point mutations to induce constitutive activation of the kinase activity of Src family kinases can readily be understood based on the three-dimensional crystal structure of downregulated Src
and Hck (see below).45,46
As noted above, the pattern of tissue expression of Src family members
varies greatly. Src is expressed in different tissues of the body with
the highest proteins levels detected in neurons and in
platelets.47 Yes is expressed primarily in neural tissues and the gastrointestinal tract.48-50 Expression of Fgr is
largely limited to monocytes and macrophages, where it plays a critical role in signaling events activated by cell adhesion.51 High levels of Fyn are observed in T lymphocytes and neural
tissue.39,52,53 Expression of Lck is largely limited to T
lymphocytes.54-56 Lyn is expressed in both myeloid cells
and B lymphocytes.57,58 In contrast, expression of Hck
(" ematopoietic
 ell  inase")
is largely limited to myeloid cells,51,59,60 while high
levels of Blk ("
 ymphocyte
inase") are present in B
lymphocytes.61 As noted above, most of these kinases are
expressed in two different isoforms and the patterns of expression may
vary for each isoform. Many of these conclusions have been reached
through the study of hematopoietic cell lines, and the true pattern of
expression in cells isolated from animals or donors may vary. Although
we have noted the cell types in which maximal expression is observed, low level of expression of Src family members may occur in many different cell types and could play an important physiological role.
Despite these qualifications, several Src family members are often
expressed in the same cell type.
| |
STRUCTURAL FEATURES OF Src-LIKE KINASES |
Like many other molecules involved in signal transduction, Src family
kinases consist of modules, which mediate protein-protein interactions.
In fact, two of these motifs, the SH2 and the SH3 domains, were first
defined in Src family kinases. Five distinct regions of a typical Src
family member are recognized as being important in protein function,
and are shown in Fig 2. These
regions include the kinase or SH1 domain, the SH2 domain, the SH3
domain, the unique domain, and the SH4 domain. The kinase domain was
the first region of homology identified among different Src family members, and it contains specific motifs common to all known protein kinases.62 The SH2 domain is approximately 100 amino acids
long and binds to phosphorylated tyrosine residues in a
sequence-specific context.63-65 The SH3 domain contains
approximately 75 amino acids and binds to proline-containing
sequences.65-67 The unique region of Src-like kinase
includes approximately 75 amino acids that are not conserved among
different Src-like kinases. Although the precise function of the unique
domain is not currently clear, there are two examples of specific
functions that correlate with specific amino acid sequences present in
the unique domain. The unique region of Lck permits its association
with CXCXXXXC motif found in CD4,68 and the
N-terminus of Lyn and Fyn binds to the nonphosphorylated
immunoreceptor tyrosine activation motif (ITAM) in the B-cell
receptor.69 The N-terminal seven residues comprise the SH4
domain of the molecule, which contains potential fatty acylation sites
required for association of Src kinases with the plasma
membrane.70,71 The glycine residue at position 2 serves as
an acceptor site for myristate, and the cysteine residue at position 3, found in all family members except Src and Blk, serves as an acceptor
site for palmitate. Palmitoylation, which is reversible, may serve
several purposes. It may serve to strengthen the association of the
kinase with the membrane. Alternatively, palmitoylation could serve to
concentrate Src family kinases in caveolae and thereby allow them to
function as effectors for glycanphosphatidylinositol-linked surface
proteins.
View larger version (10K):
[in this window]
[in a new window]
View larger version (136K):
[in this window]
[in a new window]
View larger version (27K):
[in this window]
[in a new window]
| Fig 2.
Structural-functional feature of Src. (A)
Linear diagram of an Src kinase, eg, Lyn, illustrates structural motifs
common to all Src-related kinases. Lyn consists of an N-terminal region
that undergoes posttranslational addition of fatty acid(s), a unique
region, an SH3 domain, an SH2 domain, a tyrosine kinase catalytic
domain, and a C-terminal regulatory region containing the tyrosine
(Tyr508). A conserved lysine (Lys275) is responsible for binding ATP.
There is also a positive tyrosine phosphorylation site (Tyr397). The
fatty acylation involves myristate for all Src kinases and palmitate
for all but Src and Blk. (B) Ribbon diagram based on the
crystallographic analysis of Hck. Physical analysis of Hck showed a
novel regulatory mechanism. In addition to confirming the SH2
interaction with the C-terminal phosphotyrosine, the SH3 domain
recognizes a previously unappreciated poly-proline helix II found
between the SH2 and the catalytic domains. Note that the
crystallographic studies were performed on purified Hck which, for
technical reasons, could not include the unique and N-terminal regions.
(Reprinted with permission from Nature: Sicheri
F, Moarefi I, Kuriyan J: Crystal structure of the src family tyrosine
kinase hck. Vol. 385, p. 602, 1997. Copyright 1997 Macmillan Magazines
Limited.46) (C) Activation model of Src. Src kinases are
found in either an active or inactive state depending on intramolecular
associations. Interactions occur between the SH3 domain and
poly-proline helix II motif and the SH2 domain and the C-terminal
phosphotyrosine residue. These associations, which prevent activation
of a Src kinase, are broken principally with the dephosphorylation of
the C-terminal phosphotyrosine by a protein tyrosine phosphatase
(PTP'ase).
|
|
Another critical structural feature of all Src-like kinases is the
conserved C-terminal tyrosine residue which plays a critical role in
regulating their catalytic activity. Dephosphorylation of this
tyrosine, or the binding of antibodies to the C-terminus, results in
the catalytic activation of the Src-related kinases.72,73 Phosphorylation of this C-terminal tyrosine is mediated by csk ("- rc
inase").74,75 Csk inhibition
of c-Src requires functional SH2 and SH3 domains of c-Src, suggesting
that the SH2 domain binds to the C-terminal phosphotyrosine in a manner
that is stabilized by the SH3 domain.76 Thus on the
simplest level, it could be argued that the activation of Src-related
kinases merely requires dephosphorylation of the C-terminal tyrosine by
an unidentified protein tyrosine phosphatase (PTPase).
Indeed, it has been suggested that the requirement for transmembrane
PTPase CD45 in signal transduction by the T-cell receptor reflects the
need for dephosphorylation of this regulatory tyrosine in the
activation of Src-like kinases.77-80
The crystal structures of the downregulated forms of Src and Hck have
been recently determined (Fig 2).45,46 The region of the
protein characterized included the SH3 domain, the SH2 domain, the
kinase domain, and the C-terminal tail with the regulatory tyrosine
residue phosphorylated. These studies showed that the C-terminal
phosphotyrosine residue bound to the SH2 domain in an intramolecular
fashion. The kinase domain was found to be composed of two lobes in a
fashion similar to that observed with cyclic adenosine monophosphate
(AMP)-dependent protein kinase and cyclin-dependent protein kinase
2.45,46 The adenosine triphosphate (ATP)-binding site is
present in the smaller N-terminal lobe while the active site is present
in the larger more C-terminal lobe. Contrary to the expectation that
the binding of the SH2 domain to the C-terminal tyrosine
would block access to the active site, the kinase domain and the SH2
domain were on opposite faces of the molecule. The SH3 domain was
observed to bind to the region that links the kinase domain to the SH2
domain, even though this region of the protein does not contain a
predicted SH3 domain binding site. The binding of the SH3 domain to
this linker peptide disrupts the structure of the kinase domain
rendering it inactive. This is largely accomplished through the
displacement of "helix C" which forces Glu310, a
critical residue in catalysis, out of the catalytic pocket. The
structure of downregulated Src and Hck clearly indicates that both the
SH2 and SH3 domains play important roles in the regulation of Src-like
kinases. This is consistent with data showing that point mutants in the
SH2 and SH3 domains can lead to the oncogenic activation of c-Src.
Furthermore, structural changes that prevent the interaction of either
the SH3 or the SH2 domains with other regions of the kinase molecules
can alter the regulation of the kinase. This is most easily
demonstrated by mutation of the C-terminal tyrosine to phenylalanine
which results in the constitutive activation of the
kinase.81-83 Also consistent with this concept, it has been shown that binding of the SH3 domain of Hck to the HIV Nef protein results in the catalytic activation of Hck.84 This clearly
indicated that binding of the SH3 domain to a ligand can activate
Src-like kinases. The dephosphorylation of the C-terminal
tyrosine residue, displacement of the SH2 domain from the C-terminal
phosphotyrosine of the kinase, or binding of the SH3 domain of the
enzyme to another protein represent molecular events that can lead to
activation of the enzyme by altering the three-dimensional structure of
the molecule and allowing the enzyme to assume an active conformation.
| |
Src-LIKE KINASES REGULATE CELL-CYCLE PROGRESSION |
Although it has been known for many years that the constitutive
activation of Src-like kinases leads to the oncogenic transformation of
cells, the role played by these kinases in normal cellular physiology
is just recently becoming clearer. The contribution of Src kinases to
cell-cycle progression has been established from reports of Src's
structural and functional interaction with receptor tyrosine kinases in
nonhematopoietic cells. Recent studies have shown the activation of
Src-like kinases in the G1 phase after stimulation of cells with
platelet-derived growth factor (PDGF), epidermal growth factor (EGF),
colony-stimulating factor-1, and fibroblast growth
factor.85-88 Microinjection of antibodies directed against
Src or Fyn, or of dominant negative mutants of Src or Fyn, blocked
mitogenesis induced by PDGF.86,87 Both Src and Fyn bind to
a specific phosphorylated tyrosine residue present in the cytoplasmic
tail of the PDGF receptor, and phosphorylated peptides based on this
sequence were capable of activating Src and Fyn.89 In
hematopoietic cells, the best-studied interaction of receptor and
nonreceptor tyrosine kinase has been that between c-Kit and Lyn. A
member of the same subfamily of receptors as that for PDGFR and CSF-1R,
c-Kit, when stimulated, leads to the activation of Lyn and
their association. Targeting of Lyn by either lyn antisense or
specific Src kinase inhibitor resulted in a dramatic decrease of
SCF-induced proliferation.90 We have recently reported that
the presence or absence of Lyn correlated with G-CSF-induced proliferation in hematopoietic cells (see below).91
The inhibition of PDGF-induced mitogenesis mediated by dominant
negative mutants of Src or Fyn could be rescued by the overexpression of c-myc,92 suggesting that Src-like kinases may be
required for induction of the immediate early gene c-myc and
progression through G1 to S phase. Activation of Src, Fyn, and Yes has
been noted in G2 phase and may be required for the G2 to M phase
transition.93 The activated form of cyclin-dependent kinase
Cdc2, which functions at the G2/M checkpoint, associates with Fyn, Lck,
and Lyn.94 When cells have been subjected to ionizing
radiation, Lyn's association with Cdc2 correlated with inhibition of
the Cdc2 kinase.95,96
| |
DEVELOPMENTAL IMPORTANCE OF Src: INSIGHTS GAINED FROM KNOCKOUT MICE
AND CELL LINES |
The generation of mice bearing homologous disruption of different Src
family member genes has resulted in mice with specific developmental
defects and/or diseases (Table 2).
To date the disruption of both alleles of a single Src family member
has not proved lethal, although the disruption of csk has been
lethal.97 In a few cases (fgr /, yes/,
and hck/), the knockout mice have very subtle
defects.98,100 When these mice were cross-bred to create
double knockouts, more pronounced defects were
unmasked.98,100 Thus, while gene targeting may show
important clues about the function of a specific Src family member,
conclusions about specific function must be tempered by the recognition
that there appears to be redundancy in the function of different family
members, as well as developmental variation in levels or tissue
expression of specific Src kinases. In addition, it is possible that
some of the phenotypes observed in knockout mice may be species
specific.
Mice deficient in Src develop severe osteopetrosis.53 The
defect in bone development is caused by a nonredundant contribution of
Src to proper osteoclast function. Src-deficient osteoclasts cannot
resorb bone, which may be due to a defect in their failure to form a
ruffled border.101,102 Expression
of kinase-defective alleles of Src in Src-deficient mice ameliorated
the osteopetrosis.103 These findings suggest that regions
of Src other than the kinase domain play a critical role in
cytoskeletal rearrangement and cell shape (see below). Other
nonredundant contributions by Src may not be observed because of the
increased mortality of Src/ mice. Because osteoclasts are derived
from monocyte lineage, it may not be surprising that CSF-1-deficient
mice (op/op) also develop osteopetrosis.53,104 No
patients with osteopetrosis have yet been identified with defects in
either the Src protein tyrosine kinase or in the production of CSF-1.
This highlights the problem that phenotypes observed in genetically
altered mice may not directly correspond to genetic changes that
contribute to disease in humans.
The critical importance of several different Src family members in
lymphocyte development is shown in three different knockout mice. Mice
deficient in Lck have reduced number of thymocytes,105 whereas mice deficient in Fyn have reduced T-cell receptor
responsiveness.106 Mice deficient in Lyn have reduced
number of mature B cells and aberrant B-cell receptor
signaling.106a,106b Signaling by the high-affinity IgE
receptor is also defective in lyn-deficient
mice.106a,106b
Signal transduction in myeloid cells is also defective in mice bearing
disruption of Src-family kinases. Neutrophils from hck/fgr/ mice display incompetent integrin receptor
signaling.107 Erythrocytes from these mice have higher mean
corpuscular hemoglobin due to enhanced K/Cl cotransport
activity.108 The failure to detect more profound defects in
myeloid-derived cells with single or combinational disruptions of the
genes for hck, fgr, and lyn is most likely due to
redundancy of Src kinases. Cytokine receptor signal transduction is
defective, however, in cell lines that lack expression of specific Src
family members, or in cells that express specific dominant negative
mutants of Src family kinases (discussed below).
| |
PROTEIN TYROSINE KINASE SIGNALING CASCADES: AMPLIFICATION AND
DIVERSIFICATION |
All of the hematopoietic growth factors bind to their cognate receptors
with very high (picomolar) affinity. Because only a small number of the
receptors must be engaged to induce proliferation, differentiation,
suppression of apoptosis, or activation of differentiated cell
function, signals activated by ligand binding require amplification. The phosphorylation of tyrosine residues provides a unique
amplification signal because (1) phosphotyrosine normally comprises
less than 0.05% of total phosphoamino acids,109-111
implying that this is a relatively rare modification; and (2) the
binding of SH2 domain-containing proteins to phosphotyrosine residues
allows the rapid assembly of signaling complexes. As a result of the
tyrosine phosphorylation, downstream signaling complexes are activated
or suppressed (as in the case of protein tyrosine phosphatases),
leading to a diversification and amplification of the initial signal.
Ultimately these signals are transmitted to the nucleus where changes
in gene transcription occur leading to proliferation, differentiation,
and modulation of apoptosis. Other parallel signaling cascades can
result in dramatic changes in cell shape, migration, and adhesion.
As shown in Fig 2, the structure of a Src-like kinase consists of
catalytic and noncatalytic domains. Both parts of the molecule contribute to generating and diversifying signaling cascades by trapping specific substrates and through the formation of multi-protein complexes. Although an Src family tyrosine kinase might be expected to
have a diversity of substrates, multiple factors appear to be important
in the selection of the proteins that are actually phosphorylated in a
particular cell. Factors include membrane localization of Src family
members through posttranslational addition of myristate ± palmitate, the binding of the SH2 and/or the SH3 domains of Src
family members to potential substrates or adapter molecules which
themselves are bound to substrates, and, finally, the presence of
preferred phosphorylation sites. The ability to predict proteins that
may be substrates for specific Src family members is complicated by the
contribution of each of these different factors. Degenerate peptide
library screening has been used to identify the preferred
phosphorylation sequence for Src as EEEIYG/EFD.112 However,
none of the proteins identified as likely Src substrates (Table
3) contain this phosphorylation sequence.
Although this approach has not been useful in predicting preferred
protein substrates for Src family members, it has suggested that there
are significant differences in the preferred phosphorylation sequences
for different Src-like kinases. For example, the preferred
phosphorylation site for Lck is XEXIYGV (with = L, V, F, or
I and X is indiscriminate) while that for Src is EEEIYG/EFD. The
logical explanation for our inability to predict specific substrates
based on amino acid sequence analysis is that binding of the SH3
and/or SH2 of the kinases to potential substrates are major
determinants in substrate selection and result in the phosphorylation
of "suboptimal" phosphorylation sites. SH3 domains bind to
proline-rich motifs with moderate affinity (micromolar),64-66 however, SH2 domains can bind with
nanomolar affinity to phosphotyrosine residues in a
sequence-specific context.63,64 Thus, the interactions of
SH3 and SH2 domains with proteins have a major effect on substrate
selection.
SH2 and SH3 domains are found in a wide range of proteins including
non-Src-related protein tyrosine kinases, cytoskeletal proteins,
transcription factors, and adaptor molecules. Peptide library screening
has been used to identify the preferred binding sites for the SH2
domains from many different proteins. SH2 domains have been determined
to recognize phosphorylated tyrosine residues in a sequence specific
context with the three amino acids that lie C-terminal the tyrosine
residue being critical in determining which specific SH2 domain will
being to a specific phosphotyrosine.63,64 This information
has proved to be very useful in predicting whether the SH2 domain of a
specific protein will bind to the phosphorylation site in a second
molecule. Peptide library screening113 and
screening of phage display libraries114-117 have been used
to develop consensus sequences to which different SH3 domains might
bind. These sequences all adopt a poly-proline type II helix
conformation.118 The proline-rich motif RPLPXLP is a
generic poly-proline motif that has been defined as a SH3 binding site
by phage display methods, but significant differences exist between the
sites predicted to be favored by different Src family SH3
domains.104-107 It is clear that SH3 domains may recognize
other unrecognized motifs because the analysis of downregulated Src
(described above) showed that the SH3 domain of Src can recognize a
motif within itself which structurally resembles a poly-proline type II
helix but does not contain the minimal Pro-X-X-Pro
sequence.45,46
One of the most accurate approaches to identifying substrates for Src
family members has been to express the oncogenic forms of these kinases
in the cell of interest and characterize the phosphotyrosine-containing
proteins present in these cells. One consideration inherent in this
approach is that the identified phosphorylated proteins may represent
those that are present in the highest concentration and thus may not
reflect the critical substrates. Another important consideration is
that the proteins phosphorylated in different cell types may vary
considerably. This was pointed out by a study in which the tyrosine
phosphorylated proteins present in v-Src-transformed NIH3T3 cells were
compared with those present in the murine myeloid cell line 32Dc13
expressing v-Src.119 This study concluded that either there
were substantial differences in the proteins phosphorylated or that the
proteins phosphorylated by v-Src in fibroblasts were missing from
myeloid cells. The phosphorylation of p125Fak, p120, and p85 observed in v-Src transformed 32Dc13 cells using antibodies directed against these proteins. A second approach that has been used is to employ cells
that lack the expression of either all known Src family members, or
cells that lack expression of a specific Src kinase. The latter cell
lines include fibroblast cell lines derived from knockout mice, or
cells derived from embryonic stem cell lines lacking both alleles of
specific Src kinases. An alternative, but less accurate, method is to
look for in vitro phosphorylation using recombinant Src and candidate
substrates.
By initiating signaling cascades, Src kinases affect cell shape,
migration, adhesion, cell-cycle progression, secretion, and differentiation. These responses occur through the recruitment of a
second level of signaling molecules. As a result, pathways emanating
from Ras, PI 3-Kinase, and focal adhesion kinase (Fak) are activated.
The role of Src in these signaling pathways is to either phosphorylate
the signal transduction molecule itself (eg, Fak) or to phosphorylate
an adaptor molecule (eg, Cbl and Shc) that links Src to specific
signaling molecules (PI 3-kinase and Ras, respectively). Activation of
Ras, PI 3-kinase, and nonreceptor protein tyrosine kinases such as
Zap70/Syk, Tec, and Fak cascades lead to an amplification of signals
along different signaling pathways.
The Ras and PI 3-kinase cascades recruit serine/threonine kinases,
which control proliferation, differentiation, and apoptosis. Src
activates Ras via a domino effect mediated by SH2 and SH3 interactions:
Src  Shc Grb2 Sos Ras. Loss of Shc phosphorylation in
lyn-deficient cells and the coprecipitation of Lyn and Shc show
the critical role played by Src kinases in initiating this cascade.120,121 Overexpression of Fyn increases Sos
activity, which is associated with complex formations of Fyn-Shc,
Shc-Grb2, and Grb2-Sos.122 Ras may also be activated by Src
kinases via PI 3-kinase and Fak (see below). In turn, Ras triggers a
serine/threonine kinase cascades consisting of Raf Map Kinase
Kinase Map Kinase S6 Kinase. PI 3-kinase is a heterodimeric
complex, consisting of a p110 catalytic subunit and a p85 regulatory
subunit. The latter contains two SH2 and one SH3 domains. PI 3-kinase
becomes activated via adaptor molecules, such as Cbl, and produces
3 -phosphatidylinositides. This lipid species, which is resistant to
phosphodiesterase, serves as a docking site for proteins containing a
pleckstrin domain. One such protein is the proto-oncogene product Akt,
also a serine/threonine kinase. Recent studies suggest that Akt
negatively regulates apoptosis through its phosphorylation of Bad, a
Bcl-2 binding partner.123
Src kinases activate and/or associate directly with other
nonreceptor protein tyrosine kinases, such as Zap70/Syk, Tec/Btk, and
Fak/Raftk. As a result of Src-mediated phosphorylation of immunoreceptor tyrosine activation motifs, found in components of
T-cell receptor, B-cell receptor, and Fc receptor complexes, Zap70 or
Syk become activated. The Src kinases phosphorylate the two tyrosine
residues found in the ITAM, which then serves as a docking site for the
two SH2 domains found in Zap70/Syk. As a result of this dual
phosphotyrosine-SH2 association, the kinases become activated. Major
substrates of these kinases are phospholipase C and Vav, which
recruit additional signaling cascades. Tec, Btk, and Itk comprise
another family of nonreceptor protein tyrosine kinases. In addition to
containing an SH2 and an SH3 domain, the Tec family of kinases has two
unique features: a pleckstrin domain and a Tec homology domain, which
mediates association of Tec with Lyn.124 Stimulation by
Epo, G-CSF, IL-3, and SCF leads to tyrosine phosphorylation of Tec.
Cytokine-induced association of Tec and p85 provides means by which
PI3-kinase may be activated.125 Src kinases regulate the
cytoskeleton via multiple signal transduction molecules. Src kinases
also regulate the cytoskeleton, mostly through its association with
paxillin and the nonreceptor protein tyrosine kinase Fak was first
identified in cells transformed with v-Src.126,127 Whereas
Zap70/Syk and Tec family of kinases are predominantly found in
hematopoietic tissues, Fak is more ubiquitously expressed. Engagement
of integrins results in activation of Fak.128-130 In
activated Fak, the phosphorylated tyrosine residue (Tyr397)
becomes a docking site for an Src SH2 domain,130,131 and
for the binding of the p85 subunit of PI3 kinase.119 The
recruitment of Src is critical for the role of Fak in promoting the
formation of focal adhesions, as evidenced by defective adhesion
properties in fibroblasts derived from Src-deficient
mice.131 Activation of the Ras pathway appears to occur via
binding of the SH2 domain of Grb2 to Tyr925 of
Fak.132,133
| |
Src-RELATED KINASES IN HEMATOPOIESIS AND CYTOKINE-STIMULATED
PROLIFERATION OF HEMATOPOIETIC CELLS |
Several lines of evidence suggest a critical role for Src-related
kinases in blood cell function: (1) Half of the eight known mammalian
Src kinases (Blk, Hck, and Lck) are found exclusively, and two others
(Fyn and Lyn) are predominantly found in blood cells. (2) Knock-out
mice bearing disruption of several of the Src-related genes (Fyn, Lck,
Lyn, and Hck/Fgr) display prominent hematologic
abnormalities.98,105-109 (3) Defects in Src-related kinases
have been observed in patients with hematologic disease. A patient with
T-cell acute lymphoblastic leukemia has been described with a
chromosomal translocation t(1;7)(p34;q34) that resulted in the fusion
of the lck gene with the gene encoding the  subunit of the
T-cell receptor.134 Also, defects in the closely related protein tyrosine kinases, ZAP-70 and Btk, play a critical role in
either severe combined immunodeficiency or X-linked
agammaglobulinemia.135-138 (4) Src tyrosine kinase
inhibitors block blood cell function or leukemic cell
growth.139 (5) Several different Src family kinases have
been observed to co-precipitate with hematopoietin/cytokine receptors21-25,140 or transmembrane receptor tyrosine
kinases.85,86,87,90
As noted above, a wide range of hematopoietic growth factors also
stimulate the activation of Janus family kinases. The importance of
Janus family kinases is underscored by the association of defects in
Jak3 with some forms of severe combined immunodeficiency, the generation of a novel fusion protein involving Jak2 in some forms of
T-cell leukemia.28,29,31,32,141-143 Janus family kinases
also associate with hematopoietin/cytokine
receptors.12,14,15,144,145 In the absence of ligand
binding, Janus kinases are not tyrosine-phosphorylated or catalytically
active. After cytokine stimulation, Janus kinases are rapidly
phosphorylated and activated, suggesting that they are critical in
cytokine receptor mediated signaling events. Expression of a dominant
negative form of Jak2 inhibits Epo-sensitive apoptosis in FDCP-1 cells
or suppresses GM-CSF-induced c-Fos and c-Myc promoter activities in
Ba/F3 cells.146,147 Studies with cells lines lacking specific Janus kinase family members clearly indicate that they play a
critical role in cytokine receptor signaling.30-32,146-149
Genetic deficiency of Jak2 by gene targeting profoundly inhibits Epo or IL-3-mediated hematopoiesis, but leaves G-CSF-induced myeloid colony
formation undisturbed.30,31
The biological basis of the difference between Epo/IL-3 and G-CSF
signaling rests on receptor-activated signaling components caused by
differences in receptor structure and the precise role that a Jak or
Src kinase plays in cellular physiology. It is our view is that
although activation of Janus kinases is important in cytokine-mediated
signaling events, the main mitogenic response to cytokines is mediated
by activation of Src family members.
One of the approaches we have used to examine the role of Src family
members in cytokine receptor signaling is to utilize the DT40 cell
line. DT40 is a chicken B-lymphocyte cell line that is notable because
it undergoes homologous recombination at a high rate, thereby
facilitating the disruption of genes in this cell line. In addition,
the only known Src kinase family member expressed in these cells is
Lyn.150 Expression of Lyn has been disrupted by homologous
recombination to yield the D33-3 cell line. Likewise, variants of DT40
cells have been generated which lack Syk, or Lyn and Syk expression.
Ectopic expression of the receptors for either G-CSF or GM-CSF has been
achieved in both the DT40 and the lyn-deficient D33-3 cell
line91 (and unpublished data, S.M.A., September
1998). Both G-CSF or GM-CSF can stimulate DNA synthesis in
DT40 cells expressing the cognate cytokine receptor. Conversely,
neither cytokine was able to stimulate the proliferation of the
lyn-deficient cells above background levels91 (and
unpublished data, S.M.A., September 1998). Cytokine
stimulation of lyn-deficient cells expressing either receptor
resulted in activation of Jak2 and STAT5, indicating that cytokine
stimulation of these cells activated these molecules, but this was not
sufficient to induce cytokine-dependent proliferation91
(and unpublished data, S.M.A.). Transfection of Lyn-deficient cells
with a Lyn-encoding expression vector restored cytokine-induced DNA
synthesis in these cells. These data clearly provide significant
evidence that cytokine-induced proliferation requires activation of
Src-like kinases and that activation of Jak2 and STAT5 is not
sufficient to support mitogenesis. This also suggests that the
activation of Src family members occurs downstream of Jak2, or that it
occurs independently of Jak2 in these two receptor systems. Analysis of
the substrates activated in Lyn-deficient cells indicates that the
cytokine-induced phosphorylation of Cbl and the activation of
PI3-kinase are negligible in G-CSF-stimulated Lyn-deficient cells. Ras
activation, as determined by an increase in GTP-bound Ras, was not
suppressed in the Lyn-deficient cells (unpublished data, S.J.C.,
September 1998).
Additional groups have found that either Jak activation is neither
sufficient nor necessary for cytokine-induced proliferation or
differentiation. A Tpo receptor mutant has been made that does not
activate either Jak2 or Stat family members, but is able to induce
mitogenesis.151 Expression of a dominant negative Jak2 did
not affect IL-3-induced proliferation of 32D cells, although it did
accelerate apoptosis upon IL-3 withdrawal.152 An essential role for Lyn has been established with the discovery that the mutant
J2E line, which failed to differentiate in response to Epo, is
deficient in lyn.153 At the same time that Jak
activation is not needed for all hematopoietic signaling responses,
evidence is accumulating that Src kinases can activate Stats in
hematopoietic and nonhematopoietic cells.154-157
Altogether, these reports suggest that either Jak activation precedes
that of Src in a hierarchical series or Jak and Src kinases are
activated independently.
| |
A MODEL FOR HOW Src-LIKE KINASES MIGHT BE REGULATED IN RESPONSE TO
CYTOKINE STIMULATION |
Perhaps the most critical issue in understanding signal transduction by
cytokine receptors is how the receptor induces activation of Jak and
Src family. The mechanism(s) whereby these kinases interact or bind to
the receptor must be elucidated. Although we do not fully understand
this process, clues are starting to accumulate. It is clear that Jaks
physically associate with and can be coprecipitated with multiple
cytokine receptors.12,14,15,144,145 In those cases where
physical association has not been observed, it is likely to be caused
by experimental artifact. One or more members of the Janus family are
activated by all members of the cytokine receptor family.
Activation of Janus family members appears to require the
phosphorylation of one of two tyrosine residues present in the
"activation loop" of the kinase; in the case of Jak2,
phosphorylation of Tyr1007 appears to be both necessary and
sufficient for catalytic activation.158 Phosphorylation of
the adjacent tyrosine in the activation loop, Tyr1006, is
not required. Ligand-induced dimerization of cytokine receptors appears
to be all that is required to bring two different molecules of Jak2
into immediate proximity such that they are able to transphosphorylate the critical tyrosine residue in the activation loop. Association of
Janus kinases with cytokine receptors appears to require the membrane
proximal box 1 sequence present in the cytoplasmic tail of all cytokine
receptors.159 No other kinase appears to be required for
activation of Jak2.143,144,160 This model would be
consistent with the mechanisms by which other tyrosine kinases, such as
the receptors for fibroblast growth factor and insulin, become
activated.161,162 Dimerization is critical for function,
and if it occurs inappropriately, it turns the kinase into an oncogene.
Ligand-independent dimerization and activation contribute critically to
leukemogenesis, as in the cases of Tel-Jak2, Tel-Abl, and Tel-PDGFR. In
these examples, the oligomerization motif of Tel provides the
mechanical basis for dimerization.163
Coprecipitation of several Src-like kinases, including Fyn, Hck, and
Lyn, with cytokine receptors has been described; this includes the
receptors for G-CSF, GM-CSF/IL-3/IL-5, Epo, IL-6, and
prolactin.21,25,129 This association has generally been described as ligand-dependent or independent; these differences may be
a reflection of the lysis conditions and the antibodies used in these
studies. The constitutive association of Hck with the murine IL-3
receptor has been observed in studies using a monoclonal antibody
directed against the cytoplasmic tail of the subunit.129 Bacterial fusion proteins containing different regions of Hck coupled to glutathionine S-transferase (GST) have been
used to demonstrate both phosphotyrosine-dependent and
phosphotyrosine-independent binding of different regions of Hck to the
subunit of the IL-3 receptor. The Hck SH2 domain was observed to
bind to the subunit in a phosphotyrosine-dependent manner, while
the Hck SH3 domain bound in a phosphotyrosine-independent
manner.140 A GST fusion protein containing a 236-amino acid
region of the cytoplasmic tail of the murine subunit was used to
localize the region(s) of phosphotyrosine-dependent and
phosphotyrosine-independent binding of Hck and the subunit.140 This region of the cytoplasmic tail of the
murine subunit has four tyrosine residues; however, none of them
would be predicted to be binding sites for the SH2 domain of Src family
kinases. Three of these four tyrosine residues are conserved in the
human c subunit, although these sequences are not
conserved among other cytokine receptors. There are several poly-proline sequences that could represent binding sites for the SH3
domains of Fyn or Lyn. A more direct approach to determining receptor-kinase interaction lies in using yeast two-hybrid in vivo
screening. Tilbrook et al153 reported that the EpoR
interacted with Lyn using this approach. However, our own studies have
not detected an interaction between Lyn or Jak2 and either the G-CSF receptor or the subunit of the GM-CSF receptor (unpublished data,
S.J.C., September 1998).
Based on these data we propose two models whereby Src and Janus kinases
transduce hematopoietin cytokine receptor signaling. In the first model
(Fig 3A), Src and Janus kinases are in
parallel. Src family tyrosine kinases are constitutively associated
with cytokine receptors in a weak interaction based on the binding of
the SH3 domain, and perhaps also the unique domain, of the kinase to
specific sequences present in the cytoplasmic tail of the receptor.
After ligand binding the receptors undergo ligand-induced dimerization.
Activation of Src-like kinases might proceed in the same manner
described above for the activation of Janus family kinases, ie,
receptor dimerization brings two different Src kinases into close
proximity so they can phosphorylate the critical tyrosine residues
present in the activation loop of the Src kinase. In this model,
activation of Src is totally independent of Jak2. In the second model
(Fig 3B), Src lies downstream of Jak. Receptor dimerization leads to
the activation of Jak2, which results in the phosphorylation of
multiple sites in the cytoplasmic tail of the receptor. The
phosphorylation of one or more specific tyrosine residues in the
cytoplasmic tail of the receptor now presents an alternative binding
site for the SH2 domain which displaces the C-terminal phosphotyrosine
from the SH2 domain binding site. The release of the C-terminal
tyrosine residue results in the catalytic activation of the Src-like
kinase. Although the precise details of the binding of Hck to the subunit of the IL-3 receptor are not known, how cytokine receptors
interact with which protein tyrosine kinase(s) remains one of the most
important issues in hematopoietic cell signaling.
View larger version (26K):
[in this window]
[in a new window]
View larger version (30K):
[in this window]
[in a new window]
| Fig 3.
Models for the activation of src-like kinases by the
hematopoietic growth factor (HGF) receptor. In (A), Src and Janus
kinases act in parallel. Src kinases are weakly associated with the
receptor, perhaps via the SH3 domain of the kinase binding to
proline-rich sequences in the cytoplasmic tail of the receptor
and/or by the binding of the unique domain to unidentified
peptide sequences. Ligand-induced receptor dimerization brings the
kinase domains of two different Src-like kinases into close proximity,
allowing the transphosphorylation of tyrosine residues in the
activation loops of the kinases. This may result in a change in the
structure of Src-like kinases such that the C-terminal regulatory
tyrosine residue is released from the SH2 domain, dephosphorylated by a
protein tyrosine phosphatase such as CD45, and the kinase is then fully
activated. After HGF stimulation, activation of Jak2 occurs
independently of Src and is mediated by phosphorylation of
Tyr1007 in Jak2. This phosphorylation results when two
molecules of Jak2 are brought into close proximity after receptor
dimerization. In (B), Src and Janus kinases act in series, with Src
being downstream of Jak. The Src-like kinases are weakly associated
with the cytokine receptor, as suggested above. The SH2 domain of the
Src-like kinase is bound to the C-terminal tyrosine residue holding the
kinase in an inactive conformation. Ligand-induced dimerization leads
to the activation of nonreceptor protein tyrosine kinases, such as
Jak2, which phosphorylate different tyrosine residues in the
cytoplasmic tail of the receptor. The SH2 domain of the Src kinase
binds to one of the newly phosphorylated tyrosine residues in the
C-terminal tail of the receptor, thereby displacing the C-terminal
tyrosine residue. This results in a conformational change of the kinase
such that is it now enzymatically active. The displaced C-terminal
tyrosine residue is eventually dephosphorylated by a protein tyrosine
phosphatase such as CD45, thus helping to maintain Src in an activated
conformation. The activation of Src kinases would require prior
activation of a Janus kinase in this model.
|
|
Finally, understanding the molecular mechanisms that regulate
activation of Src-like kinases and the roles of these kinases in
mitogenesis will provide insights into novel therapeutic approaches that can be used to block proliferation of malignant or auto-reactive cells. Alternatively, this information can be used to develop approaches to stimulate hematopoietic cell proliferation in the absence
of cytokines.
| |
ACKNOWLEDGMENT |
The authors thank the members of their laboratories for their
contributions to our research programs. We thank Betsy Burton and Dr
Zalman Shapiro for comments on this manuscript.
| |
FOOTNOTES |
Submitted May 14, 1998;
accepted September 14, 1998.
S.M.A. is supported by grants from the National Institutes of Health
and the Cancer League of Colorado, and S.J.C. is supported by grants
from the National Institutes of Health, American Cancer Society, and
the Leukemia Society of America.
Address reprint requests to Seth J. Corey, MD, Division of
Hematology-Oncology, Children's Hospital of Pittsburgh, 3705 Fifth
Ave, Pittsburgh, PA 15213; e-mail: corey{at}med.pitt.edu.
| |
REFERENCES |
1.
Metcalf D:
The molecular control of cell division, differentiation, commitment, and maturation in haematopoietic cells.
Nature
339:27, 1989[Medline]
[Order article via Infotrieve]
2.
Uddin S, Fish EN, Sher D, Colamonici OR, Kellum M, Pith PMA, White MF, Platanias LC:
The IRS-pathway operates distinctively from the State pathway in hematopoietic cells and transduces common and distinct signals during engagement of the insulin or interferon-alpha receptors.
Blood
90:2574, 1997[Abstract/Free Full Text]
3.
Sherr CJ, Rettenmier CW, Sacca R, Roussel MF, Look AT, Stanley ER:
The c-fms proto-oncogene is related to the receptor for the mononuclear phagocyte growth factor, CSF-1.
Cell
41:665, 1985[Medline]
[Order article via Infotrieve]
4.
Huang E, Nocka K, Beier DR, Chu T, Buck J, Lahm H, Wellner D, Leder P, Bessmer P:
The hematopoieitic growth factor KL is encoded by the SI locus and is the ligand of the c-kit receptor, the gene product of the W locus.
Cell
63:225, 1990[Medline]
[Order article via Infotrieve]
5.
Anderson DM, Sherr CJ, Rettenmier CW, Lyman SD, Baird A, Wignall JM, Eisenman J, Rauch C, March CJ, Boswell HS, Girnpel SD, Cosman D, Williams DE:
Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms.
Cell
63:235, 1990[Medline]
[Order article via Infotrieve]
6.
Zsebo KM, Williams DA, Geissler EN, Broudy VC, Martin FN, Atkins HL, Hsu R, Birkett NC, Okino KH, Murdock DC, Jacobsen FW, Langlely KE, Smith KA, Takeishi T, Cattanach BM, Galli SJ, Suggs SV:
Stem cell factor is encoded at the SI locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor.
Cell
63:213, 1990[Medline]
[Order article via Infotrieve]
7.
Williams DE, Eisenman J, Baird A, Rauch C, Van Ness K, March CJ, Park LS, Martin U, Mochizuki DY, Boswell HS, Burgess GS, Cosman D, Lyman SD:
Identification of a ligand for the c-kit proto-oncogene.
Cell
63:167, 1990[Medline]
[Order article via Infotrieve]
8.
Lyman SD, James L, Vanden Bos T, de Vries P, Brasel K, Gliniak B, Hollingworth LT, Picha KS, McKenna HJ, Splett RR, Fletcher FA, Maraskovsky E, Farrah T, Foxworthe D, Williams DE, Beckmann MP:
Molecular cloning of a ligand for the flt3/flk2 tyrosine kinase receptor: A proliferative factor for primative hematopoietic cells.
Cell
75:1157, 1993[Medline]
[Order article via Infotrieve]
9.
Kaczarski RS, Mufti GJ:
The cytokine receptor superfamily.
Blood Rev
5:193, 1991[Medline]
[Order article via Infotrieve]
10.
Bagley CJ, Woodcock JM, Stomski FC, Lopez AF:
The structural and functional basis of cytokine activation: Lessons from the common subunit of the granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and IL-5 receptors.
Blood
89:1471, 1997[Free Full Text]
11.
Avalos BR:
Molecular analysis of the granulocyte colony-stimulating factor receptor.
Blood
88:761, 1996[Free Full Text]
12.
Argetsinger LS, Campbell GS, Yang X, Witthuhn BA, Silvennoinen O, Ihle JN, Carter-Su C:
Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase.
Cell
74:237, 1993[Medline]
[Order article via Infotrieve]
13.
Silvennoinen O, Witthuhn BA, Quelle FW, Cleveland JL, Yi T, Ihle JN:
Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction.
Proc Natl Acad Sci USA
90:8429, 1993[Abstract/Free Full Text]
14.
Witthuhn BA, Quelle FW, Silvennoinen O, Yi T, Tang B, Miura O, Ihle JN:
JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin.
Cell
74:227, 1993[Medline]
[Order article via Infotrieve]
15.
Stahl N, Boulton TG, Farruggella T, lp NY, Davis S, Witthuhn BA, Quelle FW, Silvennoinen O, Barbieri G, Pellegrini S, Ihle JN, Yancopoulos GD:
Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 B receptor components.
Science
263:92, 1994[Abstract/Free Full Text]
16.
Ihle JN, Witthuhn BA, Quelle FW, Yamamoto K, Thierfelder WE, Kreider BL, Silvennoinen O:
Signaling by the cytokine receptor superfamily.
Trends Biochem Sci
19:222, 1994[Medline]
[Order article via Infotrieve]
17.
Anderson SM, Jorgensen B:
Activation of src-related tyrosine kinases by IL-3.
J Immunol
155:1660, 1995[Abstract]
18.
Torigoe T, O'Connor R, Santoli D, Reed JC:
Interleukin-3 regulates the activity of the LYN protein-tyrosine kinase in myeloid-committed leukemic cell lines.
Blood
80:617, 1992[Abstract/Free Full Text]
19.
Corey S, Eguinoa A, Puyana-Theall K, Bolen JB, Cantley L, Mollinedo F, Jackson TR, Hawkins PT, Stephens LR:
Granulocyte macrophage-colony stimulating factor stimulates both association and activation of phosphoinositide 3OH-kinase and src-related tyrosine kinase(s) in human myeloid derived cells.
EMBO J
12:2681, 1993[Medline]
[Order article via Infotrieve]
20.
English BK, Ihle JN, Myracle A, Yi T:
Hck tyrosine kinase activity modulates tumor necrosis factor production by murine macrophages.
J Exp Med
178:1017, 1993[Abstract/Free Full Text]
21.
Ernst M, Gearing DP, Dunn AR:
Functional and biochemical association of hck with the LIF/IL-6 receptor signal transducing subunit gp130 in embryonic stem cells.
EMBO J
13:1574, 1994[Medline]
[Order article via Infotrieve]
22.
Appleby MW, Kemer JD, Chien S, Maliszewski C, Bondadaa S, Perlmutter RM:
Involvement of p59fynT in interleukin-5 receptor signaling.
J Exp Med
182:811, 1995[Abstract/Free Full Text]
23.
Pazdrak K, Schreiber D, Forsythe P, Justement L, Alam R:
The intracellular signal transduction mechanism of interleukin 5 in eosinophils: The involvement of lyn tyrosine kinase and the ras-raf- 1 -MEK-microtubule-associated protein kinase pathway.
J Exp Med
181:1827, 1995[Abstract/Free Full Text]
24.
Corey SJ, Burkhardt AL, Bolen JB, Geahlen RL, Tkatch LS, Tweardy DJ:
Granulocyte colony-stimulating factor receptor signaling involves the formation of a three component complex with lyn and syk protein-tyrosine kinases.
Proc Natl Acad Sci USA
91:4683, 1994[Abstract/Free Full Text]
25.
Clevenger CV, Medaglia MV:
The protein tyrosine kinase P59fyn is associated with prolactin (PRL) receptor and is activated by PRL stimulation of T-lymphocytes.
Mol Endocrinol
8:674, 1994[Abstract/Free Full Text]
26.
Saharinen P, Ekman N, Sarvas K, Parker P, Alitalo K, Silvennoinen O:
The Bmx tyosine kinase induces activation of the stat signaling pathway, which is specifically inhibited by protein kinase c .
Blood
90:4341, 1997[Abstract/Free Full Text]
27.
Weil D, Power M-A, Smith SI, Li CL:
Predominant expression of murine Bmx tyrosine kinase in the granulo-monocytic lineage.
Blood
90:4332, 1997[Abstract/Free Full Text]
28.
Russell SM, Tayebi N, Nakajima H, Riedy MC, Ropberts JL, Aman MJ, Migone T-S, Noguchi M, Markert ML, Buckley RH, O'Shea JJ, Leonard WJ:
Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development.
Science
270:797, 1995[Abstract/Free Full Text]
29.
Villa A, Sironi M, Macchi P, Matteucci C, Notarangelo LD, Vezzoni P, Mantovani A:
Monocyte function in a severe combined immunodeficient patient with a donor splice mutation in the Jak3 gene.
Blood
88:817, 1996[Abstract/Free Full Text]
30.
Neubauer H, Cumano A, Muller M, Wu H, Huffstadt U, Pfeffer K:
Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis.
Cell
93:397, 1998[Medline]
[Order article via Infotrieve]
31.
Parganas E, Wang D, Stravopodis D, Topham DJ, Marine J-C, Teglund S, Vanin EF, Bodner S, Colamonici OR, van Deursen JM, Grosveld G, Ihle JN:
Jak2 is essential for signaling through a variety of cytokine receptors.
Cell
93:385, 1998[Medline]
[Order article via Infotrieve]
32.
Rodif SJ, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, King KL, Sheehan KCF, Yin L, Oennica D, Johnson EM Jr, Schreiber RD:
Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biological responses.
Cell
93:373, 1998[Medline]
[Order article via Infotrieve]
33.
Chan AC, Desai DM, Weiss A:
The role of protein tyrosine kinases and protein tyrosine phosphatases in T cell antigen receptor signal transduction.
Annu Rev Immunol
12:555, 1994[Medline]
[Order article via Infotrieve]
34.
Cambier JC, Pleiman CM, Clark M:
Signal transduction by the B cell antigen receptor and its coreceptors.
Annu Rev Immunol
12:457, 1994[Medline]
[Order article via Infotrieve]
35.
Cantrell D:
T cell antigen receptor signal transduction pathways.
Annu Rev Immunol
14:259, 1996[Medline]
[Order article via Infotrieve]
36.
Cheng AM, Chan AC:
Protein tyrosine kinases in thymocyte development.
Curr Opin Immunol
9:525, 1997[Medline]
[Order article via Infotrieve]
37.
Kurosaki T:
Molecular Mechanisms in B cell antigen receptor signaling.
Curr Opin Immunol
9:309, 1997[Medline]
[Order article via Infotrieve]
38.
Jouvin MH, Numerof RP, Kinet JP:
Signal transduction through the conserved motifs of the high affinity IgE receptor FcE RI.
Semin Immunol
7:29, 1995[Medline]
[Order article via Infotrieve]
39.
Kawakami Y, Furue M, Kawakami T:
Identification of fyn-encoded proteins in normal human blood cells.
Oncogene
4:389, 1989[Medline]
[Order article via Infotrieve]
40.
Davidson D, Chow LML, Foumel M, Veillette A:
Differential regulation of T cell antigen responsiveness by isoforms of the src-related tyrosine protein kinase p59fyn.
J Exp Med
175:1483, 1992[Abstract/Free Full Text]
41.
Yi T, Bolen JB, Ihle JN:
Hematopoietic cells express two forms of lyn kinase differing by 21 amino acids in the amino acids.
Mol Cell Biol
11:2391, 1992
42.
Levy JB, Dorai T, Wang L-H, Brugge JS:
The structurally distinct form of pp60c-src detected in neuronal cells is encoded by a unique c-src mRNA.
Mol Cell Biol
7:4142, 1987[Abstract/Free Full Text]
43.
Matrinez R, Mathey-Prevot B, Bemards A, Baltimore D:
Neuronal pp60c-src contains a six amino acid insertion relative to its non-neuronal counterpart.
Science
237:411, 1998
44.
Lock P, Ralph S, Stanley E, Boulet I, Ramsay R, Dunn AR:
Two isoforms of murine hck, generated by utilization of alternative translational initiation codons, exhibit different patterns of subcellular localization.
Mol Cell Biol
15:43-63, 1995
45.
Xu W, Harrison SC, Eck MJ:
Three-dimensional structure of the tyrosine kinase c-src.
Nature
385:595, 1997[Medline]
[Order article via Infotrieve]
46.
Sicheri F, Moarefi I, Kuriyan J:
Crystal structure of the src family tyrosine kinase hck.
Nature
385:602, 1997[Medline]
[Order article via Infotrieve]
47.
Golden A, Brugge JS:
The src oncogene, in
Reddy EP,
Skalka AM,
Curran T
(eds):
The Oncogene Handbook. New York, NY, Elsevier, 1988, p 149.
48.
Zhao YH, Baker H, Walaas SI, Sudol M:
Localization of p62c-yes protein in mammalian neural tissues.
Oncogene
6:1725, 1991[Medline]
[Order article via Infotrieve]
49.
Kruger J, Zhao YH, Murphy D, Sudol M:
Differential expression of p62c-yes in normal, hyperplastic and neoplstic human epidermis.
Oncogene
6:933, 1991[Medline]
[Order article via Infotrieve]
50.
Zhao YH, Krueger JG, Sudol M:
Expression of cellular-yes protein in mammalian tissues.
Oncogene
5:1629, 1990[Medline]
[Order article via Infotrieve]
51.
Willman CL, Stewrat CC, Longacre TL, Head DR, Habbersett R, Ziegler SF, Perlmutter RM:
Expression of the c-fgr and hck protein-tyrosine kinases in acute myeloid leukemic blasts is associated with early commitment and differentiation events in the monocytic and granulocytic lineages.
Blood
77:726, 1991[Abstract/Free Full Text]
52.
Grant SGN, O'Dell TJ, Karl KA, Stein PL, Soriano P, Kandel ER:
Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice.
Science
258:1903, 1992[Abstract/Free Full Text]
53.
Soriano P, Montgomery C, Geske R, Bradley A:
Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice.
Cell
64:693, 1991[Medline]
[Order article via Infotrieve]
54.
Veillette A, Bookman MA, Horak EM, Samelson LE, Bolen JB:
Signal transduction through the CD4 receptor involves the activation of the internal membrane tyrosine-protein kinase p561ck.
Nature
338:257, 1990
55.
Lou K, Sefton BM:
Cross-linking of T-cell surface molecules CD4 and CD8 stimulates phosphorylation of the Ick tyrosine protein kinase at the autophosphorylation site.
Mol Cell Biol
10:5305, 1990[Abstract/Free Full Text]
56.
Veillette A, Bolen JB, Bookman MA:
Alterations in tyrosine protein phosphorylation induced by antibody-mediated cross-linking of the CD4 receptor of T lymphocytes.
Mol Cell Biol
10:4441, 1990
57.
Yarnanashi Y, Fukushige S, Semba K, Sukegawa J, Miyajima N, Matsubara K, Yamamoto T, Toyshima K:
The yes-related cellular gene lyn encodes a possible tyrosine kinase similar to p561ck.
Mol Cell Biol
7:237, 1987[Abstract/Free Full Text]
58.
Yamanashi Y, Mori S, Yoshida M, Kishimoto T, Inoue K, Yamamoto T, Toyoshima K:
Selective expression of a protein-tyrosine kinase, p56lyn, in hematopoietic cells and association with production of human T-cell lymphotropic virus type 1.
Proc Natl Acad Sci USA
86:6538, 1989[Abstract/Free Full Text]
59.
Holtzman DA, Cook WD, Dunn AR:
Isolation and sequence of a cDNA corresponding to a src-related gene expressed in murine hematopoietic cells.
Proc Natl Acad Sci USA
84:8325, 1987[Abstract/Free Full Text]
60.
Quintrell N, Lebo R, Varmus H, Bishop JM, Pettenati MJ, LeBeau MM, Diaz MO, Rowley JD:
Identification of a human gene (HCK) that encodes a protein tyrosine kinase and is expressed in hematopoietic cells.
Mol Cell Biol
7:2267, 1987[Abstract/Free Full Text]
61.
Dymecki SM, Niederhuber JE, Desiderio SV:
Specific expression of a tyrosine kinase gene blk in B lymphoid cells.
Science
247:332, 1992
62.
Hanks SK, Quinn AM, Hunter T:
The protein kinase family: Conserved features and deduced phylogeny of the catalytic domains.
Science
241:42, 1988[Abstract/Free Full Text]
63.
Songyang Z, Shoelson SE, Chaudhuri M, Gish G, Pawson T, Haser WG, King F, Roberts T, Ratnofsky S, Lechleider RJ, Neel BG, Birge RB, Fajardo JE, Chou MM, Hanafasa H, Schaffhausen B, Cantley LC:
SH2 domains recognize specific phosphopeptide sequences.
Cell
72:767, 1993[Medline]
[Order article via Infotrieve]
64.
Songyang Z, Shoelson SE, McGlade J, Olivier P, Pawson T, Bustelo XR, Barbacid M, Sabe H, Hanafusa H, Yi T, Ren R, Baltimore D, Patnofsky S, Feldman RA, Cantley LC:
Specific motifs recognized by the SH2 domains of csk, 3BP2, fps/fes, GRB-2, HCP, SHC, syk, and vav.
Mol Cell Biol
14:2777, 1994[Abstract/Free Full Text]
65.
Cohen GB, Ren R, Baltimore D:
Modular binding domains in signal transduction proteins.
Cell
80:237, 1995[Medline]
[Order article via Infotrieve]
66.
Ren R, Mayer BJ, Cicchetti P, Baltimore D:
Identification of a ten-amino acid proline-rich SH3 binding site.
Science
259:1157, 1993[Abstract/Free Full Text]
67.
Mayer BJ, Eck MJ:
SH3 domains. Minding your p's and q's.
Curr Biol
5:364, 1995[Medline]
[Order article via Infotrieve]
68.
Turner JM, Brodsky MH, Irving BA, Levin SD, Perlmutter RM, Littman DR:
Interaction of the unique-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs.
Cell
60:755, 1990[Medline]
[Order article via Infotrieve]
69.
Pleiman CM, Abrams C, Gauen LT, Bedzyk W, Jongstra J, Shaw AS, Cambier JC:
Distinct p53/p56 lyn and P59fyn domains associate with nonphosphorylated and phosphorylated Ig .
Proc Natl Acad Sci USA
91:4268, 1994[Abstract/Free Full Text]
70.
Alland L, Peseckis SM, Atherton RE, Berthiaume L, Resh MD:
Dual myristylation and palmitylation of src family member p59fyn affects subcellular localization.
J Biol Chem
269:16701, 1994[Abstract/Free Full Text]
71.
Sigal CT, Zhou W, Buser CA, Mclaughlin S, Resh MD:
Amino-terminal basic residues of src mediate membrane binding through electrostatic interaction with acidic phospholipids.
Proc Natl Acad Sci USA
91:12253, 1994[Abstract/Free Full Text]
72.
Cooper JA, Gould KL, Cartwright CA, Hunter T:
Tyr527 is phosphorylated in pp60src: Implication for regulation.
Science
231:1431, 1986[Abstract/Free Full Text]
73.
Cooper JA, King CS:
Dephosphorylation or antibody binding to the carboxy terminus stimulates pp60c-src.
Mol Cell Biol
6:4467, 1986[Abstract/Free Full Text]
74.
Okada M, Nakagawa H:
A protein tyrosine kinase involved in regulation of pp60src function.
J Biol Chem
264:20886, 1989[Abstract/Free Full Text]
75.
Sabe H, Knudsen B, Okada M, Nada S, Nakagawa H, Hanafusa H:
Molecular cloning and expression of chicken C-terminal src kinase: lack of stable association with c-src protein.
Proc Natl Acad Sci USA
89:2190, 1992[Abstract/Free Full Text]
76.
Superti-Furga G, Fumagalli S, Koegl M, Courtneidge SA, Dreatta G:
Csk inhibition of c-src activity requires both the SH2 and SH3 domains of src.
EMBO J
12:2625, 1993[Medline]
[Order article via Infotrieve]
77.
Sieh M, Bolen JB, Weiss A:
CD45 specifically modulates binding of lck to a phosphopeptide encompassing the negative regulatory tyrosine of lck.
EMBO J
12:315, 1993[Medline]
[Order article via Infotrieve]
78.
Mustelin T, Coggeshall KM, Altman A:
Rapid activation of the T-cell tyrosine protein kinase pp56 lck by the CD45 phosphotyrosine phosphatase.
Proc Natl Acad Sci USA
86:6302, 1989[Abstract/Free Full Text]
79.
Ostergaard HL, Trowbridge IS:
Coclustering CD45 with CD4 or CD8 alters the phosphorylation and lck kinase activity of p56.
J Exp Med
172:347, 1990[Abstract/Free Full Text]
80.
Mustelin T, Altman A:
Dephosphorylation and activation of the T cell tyrosine kinase pp56 lck by the leukocyte comon antigen (CD45).
Oncogene
5:809, 1990[Medline]
[Order article via Infotrieve]
81.
Kmiecik TE, Shalloway D:
Activation and suppression of pp60c-src transformation ability by mutation of its primary sites of tyrosine phosphorylation.
Cell
49:65, 1987[Medline]
[Order article via Infotrieve]
82.
Piwnica-Worms H, Saunders KB, Roberts TM, Smith AE, Cheng SH:
Tyrosine phosphorylation regualtes the biochemical and biological properties of pp60c-src.
Cell
49:75, 1987[Medline]
[Order article via Infotrieve]
83.
Reynolds AB, Vila J, Lansing TJ, Potts WM, Weber MJ, Parsons JT:
Activation of the oncogenic potential of the avain cellular src protein by specific alteration of the carboxy terminus.
EMBO J
6:2359, 1987[Medline]
[Order article via Infotrieve]
84.
Moarefi I, LaFevre-Bemt M, Sicheri F, Huse M, Lee C-H, Kuriyan J, Miller WT:
Activation of the src-family tyrosine kinase hck by SH3 domain displacement.
Nature
385:650, 1997[Medline]
[Order article via Infotrieve]
85.
Courtneidge SA, Dhand R, Pilat D, Twamley GM, Waterfield MD, Roussel MF:
Activation of src family kinases by colony-stimulating factor-1, and their association with its receptor.
EMBO J
12:943, 1993[Medline]
[Order article via Infotrieve]
86.
Twamley-Stein GM, Pepperkok R, Ansorge W, Courtneidge SA:
The src family tyrosine kinases are required for platelet-derived growth factor-mediated signal transduction in NIH 3T3 cells.
Proc Natl Acad Sci USA
90:7696, 1993[Abstract/Free Full Text]
87.
Roche S, Koegel M, Barone MV, Roussel MF, Courtneidge SA:
DNA synthesis induced by some but not all growth factors requires src family protein kinases.
Mol Cell Biol
15:1102, 1995[Abstract]
88.
Landgren E, Blume-Jensen P, Courtneidge SA, Claesson-Welsh L:
Fibroblast growth factor receptor-1 regulation of src family kinases.
Oncogene
10:2027, 1995[Medline]
[Order article via Infotrieve]
89.
Alonso G, Koegl M, Mazurenko N, Courtneidge SA:
Sequence requirements for binding of src family tyrosine kinases to activated growth factor receptors.
J Biol Chem
270:9840, 1995[Abstract/Free Full Text]
90.
Linnekin D, DeBerry CS, Mou S:
Lyn associates with the juxtamembrane region of c-Kit and is activated by stem cell factor in hematopoietic cell lines and normal progenitor cells.
J Biol Chem
272:27450, 1997[Abstract/Free Full Text]
91.
Corey SJ, Dombrosky-Ferlan PM, Zuo S, Krohn E, Donnenberg AD, Zorich P, Romero G, Takata M, Kurosaki T:
Requirement of src kinase lyn for induction of DNA synthesis by granulocyte colony-stimulating factor.
J Biol Chem
273:3230, 1998[Abstract/Free Full Text]
92.
Barone MV, Courtneidge SA:
Myc but not fos rescue of PDGF signalling block caused by kinase-inactive src.
Nature
378:509, 1995[Medline]
[Order article via Infotrieve]
93.
Roche SI, Fumagalli S, Courtneidge SA:
Requirement for src family protein tyrosine kinases in G2 for fibroblast cell division.
Science
269:1567, 1995[Abstract/Free Full Text]
94.
Pathan NI, Geahlen RL, Harrison ML:
The protein tyrosine kinase Lck associates with and is phosphorylated by Cdc2.
J Biol Chem
271:27517, 1996[Abstract/Free Full Text]
95.
Kharbanda S, Saleem A, Yuan ZM, Kraeft S, Weischelbaum R, Chen LB, Kufe D:
Nuclear signaling induced by ionizing radiation involves colocalization of the activated p56/p53lyn tyrosine kinase with p34cdc2.
Cancer Res
56:3617, 1996[Abstract/Free Full Text]
96.
Uckun FM, Tuel-Ahlgren L, Waddick KG, Jun X, Jin J, Myers DE, Rowley RB, Burkhardt AL, Bolen JB:
Physical and functional interactions between Lyn and p34cdc2 kinases in irradiated human B-cell precursors.
J Biol Chem
271:6389, 1996[Abstract/Free Full Text]
97.
Imamoto A, Soriano P:
Disruption of the csk gene, encoding a negative regulator of src family tyrosine kinases, leads to neural tube defects and embryonic lethality.
Cell
73:1117, 1995
98.
Lowell CA, Soriano PI, Varmus HE:
Functional overlap in the src family: Inactivation of hck and fgr impairs natural immunity.
Genes Dev
8:387, 1994[Abstract/Free Full Text]
99.
Lowell CA, Niwa M, Soriano P, Varmus H:
Deficiency of the Hck and Src Tyrosine kinases results in extreme levels of extramedullary hematopoiesis.
Blood
87:1780, 1996[Abstract/Free Full Text]
100.
Stein PL, Vogel H, Soriano P:
Combined deficiencies of Src, Fyn, and Yes tyrosine kinases in mutant mice.
Genes Dev
8:1999, 1994[Abstract/Free Full Text]
101.
Lowe C, Yoneda T, Boyce BF, Chen H, Mundy GR, Soriano P:
Osteopetrosis in src-deficient mice is due to an autonomous defect of osteoclasts.
Proc Natl Acad Sci USA
90:4485, 1993[Abstract/Free Full Text]
102.
Boyce BF, Yoneda T, Lowe C, Soriano P, Mundy GR:
Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice.
J Clin Invest
90:1622, 1992
103.
Schwartzberg PL, Xing LP, Hoffmann O, Lowell CA, Garrett L, Boyce BF, Varmus HE:
Rescue of osteoclast function by transgenic expression of kinase deficient src in src/mutant mice.
Genes Dev
11:2835, 1997[Abstract/Free Full Text]
104.
Wiktor-Jedrzejcak W, Urbanowska E, Aukerman SL, Pollard JW, Stanley ER, Ralph P, Ansari AA, Sell KW, Szperl M:
Correction by CSF-1 of defects in the osteopetrotic op/op mouse suggests local, developmental, and humoral requirements for this growth factor.
Exp Hematol
19:1049, 1991[Medline]
[Order article via Infotrieve]
105.
Molina TJ, Bachmann MF, Kundig TM, Zinkemagel RM, Mak TW:
Peripheral T cells in mice lacking p56lck do not express significant antiviral effector functions.
J Immunol
151:699, 1993[Abstract]
106.
Stein PL, Lee H, Rich S, Soriano P:
pp59fyn mutant mice display differential signalling in thymocytes and peripheral T cells.
Cell
70:741, 1992[Medline]
[Order article via Infotrieve]
106a.
Hibbs ML, Tarlinton DM, Armes J, Grail D, Hodgson G, Maglitto R, Stacker SA, Dunn AR:
Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease.
Cell
83:301, 1995[Medline]
[Order article via Infotrieve]
106b.
Nishizumi H, Taniuchi I, Yamanashi Y, Kitamura D, Ilic D, Mori S, Watanabe T, Yamamoto T:
Impaired proliferation of peripheral B cells and indication of autoimmune disease in lyn-deficient mice.
Immunity
3:549, 1995[Medline]
[Order article via Infotrieve]
107.
Lowell CA, Fumagalli L, Berton G:
Deficiency of Src family kinases p59/61hck and p58c-fgr results in defective adhesion-dependent neutrophil functions.
J Cell Biol
133:895, 1996[Abstract/Free Full Text]
108.
De Franceschi L, Fumagalli L, Olivieri O, Corrocher R, Lowell CA, Berton G:
Deficiency of src family kinases Fgr and Hck results in activation of erythrocyte K/Cl cotransport.
J Clin Invest
99:220, 1997[Medline]
[Order article via Infotrieve]
109.
Hunter T, Sefton BM:
Transforming gene product of Rous sarcoma virus phosphorylates tyrosine.
Proc Natl Acad Sci USA
77:1311, 1980[Abstract/Free Full Text]
110.
Sefton BM, Hunter T, Raschke WC:
Evidence that the Abelson virus protein functions in vivo as a protein kinase that phosphroylates tyrosine.
Proc Natl Acad Sci USA
78:1552, 1981[Abstract/Free Full Text]
111.
Cooper JA, Hunter T:
Changes in protein phosphorylation in Rous sarcome virus-transformed chicken embryo cells.
Mol Cell Biol
1:165, 1981[Abstract/Free Full Text]
112.
Zhou S, Carraway KL III, Eck MJ, Harrison SC, Feldman RA, Mohammadi M, Schlessinger J, Hubbard SR, Smith DP, Eng C:
Catalytic specificity of protein-tyrosine kinases is critical for selective signalling.
Nature
373:536, 1995[Medline]
[Order article via Infotrieve]
113.
Sparks AB, Rider JE, Hoffman NG, Fowlkes DM, Quilliam LA, Kay BK:
Distinct ligand preferences of src homology 3 domains from src, yes, abl, cortactin, p53bp2, PLC, crk and grb2.
Proc Natl Acad Sci USA
93:1540, 1996[Abstract/Free Full Text]
114.
Rickles RJ, Botfield MC, Weng Z, Taylor JA, Green OM, Brugge JS, Zoller MJ:
Identification of src, fyn, lyn, P13K and abl SH3 domain ligands using phage display libraries.
EMBO J
13:5598, 1994[Medline]
[Order article via Infotrieve]
115.
Rickles RJ, Botfield MC, Zhou X-M, Hanery PA, Brugge JS, Zoller MJ:
Phage display selections of ligand residues important for src homology 3 domain binding specificity.
Proc Natl Acad Sci USA
92:10909, 1995[Abstract/Free Full Text]
116.
Sparks AB, Quilliam LA, Thom JM, Der CJ, Kay BK:
Identification and characterization of src SH3 ligands from phage-displayed random peptide libraries.
J Biol Chem
269:23853, 1994[Abstract/Free Full Text]
117.
Cheadle C, Ivashchenko Y, South V, Searfoss GH, French S, Howk R, Ricca GA, Jaye M:
Identification of a src SH3 domain binding motif by screening a random phage display library.
J Biol Chem
269:24034, 1994[Abstract/Free Full Text]
118.
Yu H, Chen JK, Feng S, Dalgamo DC, Brauer AW, Schreiber SL:
Structural basis for the binding of proline-rich peptides to SH3 domains.
Cell
76:933, 1994[Medline]
[Order article via Infotrieve]
119.
Erwin JL, Anderson SM:
Analysis of phosphotyrosine-containing proteins present in v-src-infected myeloid progenitor cells.
Oncogene
7:1101, 1992[Medline]
[Order article via Infotrieve]
120.
Nagai K, Takata H, Kurosaki T:
Tyrosine phosphorylation of Shc is mediated through Lyn and Syk in B cell receptor signaling.
J Biol Chem
270:6824, 1995[Abstract/Free Full Text]
121.
Ptasznik R, Traynor-Kaplan A, Bokoch GM:
G protein-coupled chemoattractant receptors regulate Lyn tyrosine kinase Shc adapter protein signaling complexes.
J Biol Chem
270:19969, 1995[Abstract/Free Full Text]
122.
Li B, Subleski M, Fusaki N, Yamamoto T, Copeland T, Princler GL, Kung H, Kamata T:
Catalytic activity of the mouse guanine nucleotide exchanger mSOS is activated by Fyn tyrosine protein kinase and the T cell antigen receptor in T cells.
Proc Natl Acad Sci USA
93:1001, 1996[Abstract/Free Full Text]
123.
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME:
Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery.
Cell
91:231, 1997[Medline]
[Order article via Infotrieve]
124.
Mano H, Yamashita Y, Miyazato A, Miura Y, Ozawa K:
Tec protein-tyrosine kinase is an effector molecule of Lyn protein-tyrosine kinase.
FASEB J
10:637, 1996[Abstract]
125.
Takhashi-Tezuka M, Hibi M, Fujitani Y, Fukada T, Yamaguichi T, Hirano T:
Tec tyrosine kinase links the cytokine receptors to PI 3-kinase probably through Jak.
Oncogene
14:2273, 1997[Medline]
[Order article via Infotrieve]
126.
Schaller MD, Borgman CA, Cobb BS, Vines RR, Reynolds AB, Parsons JT:
ppl25FAK, a structurally distinctive protein-tyrosine kinase associated with focal adhesions.
Proc Natl Acad Sci USA
89:5192, 1992[Abstract/Free Full Text]
127.
Burridge K, Turner CE, Romer LH:
Tyrosine phosphorylation of paxillin and ppl25FAK accompanies adhesion to extracellular matrix: A role in cytoskeletal assembly.
J Cell Biol
119:8939, 1992
128.
Cobb BS, Schaller MD, Leu T-H, Parsons JT:
Stable association of pp60src and p59fyn with the focal adhesion-associated protein kinase, pp 125 FAK.
Mol Cell Biol
14:147, 1994[Abstract/Free Full Text]
129.
Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR, Parsons JT:
Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src.
Mol Cell Biol
14:1680, 1994[Abstract/Free Full Text]
130.
Chen H-C, Appeddu PA, Isoda H, Guan J-L:
Phosphorylation of tyrosine 397 in focal adhesion kinase is required for binding of phosphatidylinositol 3-kinase.
J Biol Chem
271:26329, 1996[Abstract/Free Full Text]
131.
Thomas SM, Soriano P, Imamoto A:
Specific and redundant roles of Src and Fyn in organizing the cytoskeleton.
Nature
376:267, 1995[Medline]
[Order article via Infotrieve]
132.
Schlaepfer DD, Hanks SK, Hunter T, van der Geer P:
Integrin-mediated signal transduction linked to ras pathway by GRB2 binding to focal adhesion kinase.
Nature
372:786, 1994[Medline]
[Order article via Infotrieve]
133.
Schlaepfer DD, Hunter T:
Focal adhesion kinase overexpression enhances ras-dependent integrin signaling to ERK2/mitogen-activated protein kinase through interactions with and activation or c-src.
J Biol Chem
272:13189, 1997[Abstract/Free Full Text]
134.
Tycko B, Smith SD, Sklar J:
Chromosomal translocations joining LCK and TCRB loci in human T cell leukemia.
J Exp Med
174:867, 1991[Abstract/Free Full Text]
135.
Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F, Hammarstrom L, Kinnon C, Levinsky R, Babrow M, Edvard Smith CI, Bentley DR:
The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinase.
Nature
361:226, 1993[Medline]
[Order article via Infotrieve]
136.
Arpaia E, Shahar M, Dadi H, Cohen A, Roifinan CM:
Defective T cell receptor signaling and CD8+ thymic selection in humans lacking Zap-70 kinase.
Cell
76:947, 1994[Medline]
[Order article via Infotrieve]
137.
Elder ME, Lin D, Clever J, Chan AC, Hope TJ, Weiss A, Parslow TG:
Human severe combined immunodeficienct due to a defect in ZAP-70, a T cell tyrosine kinase.
Science
264:1596, 1994[Abstract/Free Full Text]
138.
Chan AC, Kadlecek TA, Elder ME, Filipovich AH, Kuo W-L, Iwashima M, Parslow TG, Weiss A:
ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency.
Science
264:1599, 1994[Abstract/Free Full Text]
139.
Uckun FM, Evans WE, Forsyth CJ, Waddick KG, Ahlgren LT, Chelstrom LM, Burkhardt A, Bolen J, Myers DE:
Biotherapy of B cell precursor leukemia by targeting genistein to CD19-associated tyrosine kinases.
Science
267:886, 1995[Abstract/Free Full Text]
140.
Burton EA, Hunter S, Wu SC, Anderson SM:
Binding of src-like kinases to the subunit of the interleukin-3 receptor.
J Biol Chem
272:16189, 1997[Abstract/Free Full Text]
141.
Tortolani PJ, Lal BK, Riva A, Johnson JA, Chen Y-Q, Reamon GH, Beckwith M, Longo D, Ortaldo JR, Bhatia K, McGrath I, Kehrl JH, Tuscano J, McVicar DW, O'Shea JJ:
Regulation of JAK3 expression and activation in human B cells and B cell malignancies.
J Immunol
155:5220, 1995[Abstract]
142.
Peeters P, Raynaud SD, Cools J, Wlodarska 1, Grosgeorge J, Philip P, Manpoux F, Van Rompaey L, Baens M, Van den Berghe H, Maryman P:
Fusion of TEL, the ETS-varient gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9:12) in a lymphoid and t(9:15;12) in a myeloid leukemia.
Blood
90:2535, 1997[Abstract/Free Full Text]
143.
Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT, Mauchauffe M, Berthou C, Lessard M, Berger R, Ghysdael J, Bernard OA:
A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia.
Science
278:1309, 1997[Abstract/Free Full Text]
144.
Rui H, Kirken RA, Farrar WL:
Activation of receptor-associated tyrosine kinase JAK2 by prolactin.
J Biol Chem
269:5364, 1994[Abstract/Free Full Text]
145.
Lebrun J-J, Ali S, Sofer L, Ulrich A, Kelly PA:
Prolactin-induced proliferation of Nb2 cells involves tyrosine phosphorylation of the prolactin receptor and its associated tyrosine kinase JAK2.
J Biol Chem
269:14021, 1994[Abstract/Free Full Text]
146.
Watanabe S, Itoh T, Arai K:
JAK2 is essential for activation of c-fos and c-myc promoters and cell proliferation through the human granulocyte-macrophage colony-stimulating factor receptor in BA/F3 cells.
J Biol Chem
271:12681, 1996[Abstract/Free Full Text]
147.
Watling D, Guschin D, Muller M, Silvennoinen O, Witthuhn BA, Quelle FW, Rogers NC, Schinder C, Stark GR, Kerr IM:
Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon- signal transduction pathway.
Nature
366:166, 1993[Medline]
[Order article via Infotrieve]
148.
Muller M, Briscoe J, Laxton C, Guschin D, Ziemiecki A, Silvennoinen O, Harpur AG, Barbieri G, Witthuhn BA, Schindler C, Pellegrini S, Wilks AF, Ihle JN, Stark GR, Kerr IM:
The protein tyrosine kinase JAK1 complements defects in interferon-/ and - signal transduction.
Nature
366:129, 1993[Medline]
[Order article via Infotrieve]
149.
Shimoda K, Feng J, Murakami H, Nagata S, Watling D, Rogers NC, Stark GR, Kerr IM, Ihle JN:
Jak1 plays an essential role for receptor phosphorylation and Stat activation in response to granulocyte colony-stimulating factor.
Blood
90:597, 1997[Abstract/Free Full Text]
150.
Takata M, Sabe H, Hata A, Inazu T, Homma Y, Nukada T, Yamamura H, Kurosaki T:
Tyrosine kinases Lyn and Syk regulate B cell receptor-coupled Ca2+ mobilization through distinct pathways.
EMBO J
13:1341, 1994[Medline]
[Order article via Infotrieve]
151.
Dorsch M, Fan PD, Danial NN, Rothman PB, Goff SP:
The thrombopoietin receptor can mediate proliferation without activation of the Jak-STAT pathway.
J Exp Med
186:1947, 1997[Abstract/Free Full Text]
152.
Chaturvedi P, Reddy MVR, Reddy EP:
Src kinases and not JAKs activate STATs during IL-3 induced myeloid cell proliferation.
Oncogene
16:1749, 1998[Medline]
[Order article via Infotrieve]
153.
Tilbrook PA, Ingley E, Williams JH, Hibbs ML, Klinken SP:
Lyn tyrosine kinase is essential for eythropoietin-induced differentiation of J2E cells.
EMBO J
16:1610, 1997[Medline]
[Order article via Infotrieve]
154.
Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J, Jove R:
Enhanced DNA-binding activity of Stat3-related protein in cells transformed by the Src oncoprotein.
Science
269:81, 1995[Abstract/Free Full Text]
155.
Yu CL, Jove R, Burakoff SR:
Constitutive activation of the Janus kinase-STAT pathway in T lymphoma overexpressing the Lck protein tyrosine kinase.
J Immunol
159:5206, 1997[Abstract]
156.
Turkson J, Bowman T, Garcia R, Caldenhoven E, DeGroot RP, Jove R:
Stat3 activation by Src induces specific gene regulation and is required for cell transformation.
Mol Cell Biol
18:2545, 1998[Abstract/Free Full Text]
157.
Chin H, Arai A, Wakao H, Kamiyama R, Miyasaka N, Miura O:
Lyn physically associates with the erythropoieitin and may play a role in activation of the Stat5 pathway.
Blood
91:3734, 1998[Abstract/Free Full Text]
158.
Feng J, Witthuhn BA, Matsuda T, Kouber F, Kerr IM, Ihle JN:
Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop.
Mol Cell Biol
17:2497, 1997[Abstract]
159.
Quelle FW, Sato N, Witthuhn BA, Inhom RC, Eder M, Miyajima A, Griffin JD, Ihle JN:
JAK2 associates with the c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region.
Mol Cell Biol
14:4335, 1994[Abstract/Free Full Text]
160.
Nakamura N, Chin H, Miyasaka N, Miura O:
An epidermal growth factor receptor/Jak2 tyrosine kinase domain chimera induces tyrosine phosphorylation of Stat5 and transduces a growth signal in hematopoietic cells.
J Biol Chem
271:19483, 1996[Abstract/Free Full Text]
161.
Hubbard SR, Wei L, Ellis L, Hendrickson WE:
Crystal structure of the tyrosine kinase domain of the human insulin receptor.
Nature
372:746, 1994[Medline]
[Order article via Infotrieve]
162.
Hubbard SR, Mohammadi M, Schlessinger J:
Autoregulatory mechanisms in protein-tyrosine kinases.
J Biol Chem
273:11987, 1998[Free Full Text]
163.
Golub TR, Goga A, Barker GF, Afar DE, McLaughlin J, Bohlander SK, Rowley JD, Witte ON, Gilliland DG:
Oligomerization of the ABL tyrosine kinase by the ETS protein TEL in human leukemia.
Mol Cell Biol
16:4107, 1996[Abstract]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
E. Kennah, A. Ringrose, L. L. Zhou, S. Esmailzadeh, H. Qian, M.-w. Su, Y. Zhou, and X. Jiang
Identification of tyrosine kinase, HCK, and tumor suppressor, BIN1, as potential mediators of AHI-1 oncogene in primary and transformed CTCL cells
Blood,
May 7, 2009;
113(19):
4646 - 4655.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. K. Williams, I. S. Lucet, S. P. Klinken, E. Ingley, and J. Rossjohn
Crystal Structures of the Lyn Protein Tyrosine Kinase Domain in Its Apo- and Inhibitor-bound State
J. Biol. Chem.,
January 2, 2009;
284(1):
284 - 291.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Mathew, S. P. George, Y. Wang, M. R. Siddiqui, K. Srinivasan, L. Tan, and S. Khurana
Potential Molecular Mechanism for c-Src Kinase-mediated Regulation of Intestinal Cell Migration
J. Biol. Chem.,
August 15, 2008;
283(33):
22709 - 22722.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Bugarski, A. Krstic, S. Mojsilovic, M. Vlaski, M. Petakov, G. Jovcic, N. Stojanovic, and P. Milenkovic
Signaling Pathways Implicated in Hematopoietic Progenitor Cell Proliferation and Differentiation
Experimental Biology and Medicine,
January 1, 2007;
232(1):
156 - 163.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Ingley, J. R. Schneider, C. J. Payne, D. J. McCarthy, K. W. Harder, M. L. Hibbs, and S. P. Klinken
Csk-binding Protein Mediates Sequential Enzymatic Down-regulation and Degradation of Lyn in Erythropoietin-stimulated Cells
J. Biol. Chem.,
October 20, 2006;
281(42):
31920 - 31929.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. G. Karur, C. A. Lowell, P. Besmer, V. Agosti, and D. M. Wojchowski
Lyn kinase promotes erythroblast expansion and late-stage development
Blood,
September 1, 2006;
108(5):
1524 - 1532.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kim, J. Jin, and S. P. Kunapuli
Relative contribution of G-protein-coupled pathways to protease-activated receptor-mediated Akt phosphorylation in platelets
Blood,
February 1, 2006;
107(3):
947 - 954.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F.-J. Li, N. Tsuyama, H. Ishikawa, M. Obata, S. Abroun, S. Liu, K.-i. Otsuyama, X. Zheng, Z. Ma, Y. Maki, et al.
A rapid translocation of CD45RO but not CD45RA to lipid rafts in IL-6-induced proliferation in myeloma
Blood,
April 15, 2005;
105(8):
3295 - 3302.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. D. Bozulic, W. L. Dean, and N. A. Delamere
The Influence of SRC-Family Tyrosine Kinases on Na,K-ATPase Activity in Lens Epithelium
Invest. Ophthalmol. Vis. Sci.,
February 1, 2005;
46(2):
618 - 622.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. W. Harder, C. Quilici, E. Naik, M. Inglese, N. Kountouri, A. Turner, K. Zlatic, D. M. Tarlinton, and M. L. Hibbs
Perturbed myelo/erythropoiesis in Lyn-deficient mice is similar to that in mice lacking the inhibitory phosphatases SHP-1 and SHIP-1
Blood,
December 15, 2004;
104(13):
3901 - 3910.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. E. Laurent, F. J. Delfino, H. Y. Cheng, and T. E. Smithgall
The Human c-Fes Tyrosine Kinase Binds Tubulin and Microtubules through Separate Domains and Promotes Microtubule Assembly
Mol. Cell. Biol.,
November 1, 2004;
24(21):
9351 - 9358.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. L. Johnson and D. W. Bianchi
Fetal cells in maternal tissue following pregnancy: what are the consequences?
Hum. Reprod. Update,
November 1, 2004;
10(6):
497 - 502.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. J. Lannutti and J. G. Drachman
Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors
Blood,
May 15, 2004;
103(10):
3736 - 3743.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q.-S. Zhu, L. J. Robinson, V. Roginskaya, and S. J. Corey
G-CSF-induced tyrosine phosphorylation of Gab2 is Lyn kinase dependent and associated with enhanced Akt and differentiative, not proliferative, responses
Blood,
May 1, 2004;
103(9):
3305 - 3312.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. K. Mirnics, E. Caudell, Y. Gao, K. Kuwahara, N. Sakaguchi, T. Kurosaki, J. Burnside, K. Mirnics, and S. J. Corey
Microarray Analysis of Lyn-Deficient B Cells Reveals Germinal Center-Associated Nuclear Protein and Other Genes Associated with the Lymphoid Germinal Center
J. Immunol.,
April 1, 2004;
172(7):
4133 - 4141.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Cussac, C. Greenland, S. Roche, R.-Y. Bai, J. Duyster, S. W. Morris, G. Delsol, M. Allouche, and B. Payrastre
Nucleophosmin-anaplastic lymphoma kinase of anaplastic large-cell lymphoma recruits, activates, and uses pp60c-src to mediate its mitogenicity
Blood,
February 15, 2004;
103(4):
1464 - 1471.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J. Acosta, R. M. Munoz, L. Gonzalez, A. Subtil-Rodriguez, M. A. Dominguez-Caceres, J. M. Garcia-Martinez, A. Calcabrini, I. Lazaro-Trueba, and J. Martin-Perez
Src Mediates Prolactin-Dependent Proliferation of T47D and MCF7 Cells via the Activation of Focal Adhesion Kinase/Erk1/2 and Phosphatidylinositol 3-Kinase Pathways
Mol. Endocrinol.,
November 1, 2003;
17(11):
2268 - 2282.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Potoka, J. S. Upperman, X.-R. Zhang, J. R. Kaplan, S. J. Corey, A. Grishin, R. Zamora, and H. R. Ford
Peroxynitrite inhibits enterocyte proliferation and modulates Src kinase activity in vitro
Am J Physiol Gastrointest Liver Physiol,
November 1, 2003;
285(5):
G861 - G869.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. L. Tan, L. Hong, V. Munugalavadla, and R. Kapur
Functional and Biochemical Consequences of Abrogating the Activation of Multiple Diverse Early Signaling Pathways in Kit. ROLE FOR Src KINASE PATHWAY IN KIT-INDUCED COOPERATION WITH ERYTHROPOIETIN RECEPTOR
J. Biol. Chem.,
March 21, 2003;
278(13):
11686 - 11695.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Harashima, M. Suzuki, A. Okochi, M. Yamamoto, Y. Matsuo, R. Motoda, T. Yoshioka, and K. Orita
CD45 tyrosine phosphatase inhibits erythroid differentiation of umbilical cord blood CD34+ cells associated with selective inactivation of Lyn
Blood,
December 15, 2002;
100(13):
4440 - 4445.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. J. Schreiner, A. P. Schiavone, and T. E. Smithgall
Activation of STAT3 by the Src Family Kinase Hck Requires a Functional SH3 Domain
J. Biol. Chem.,
November 15, 2002;
277(47):
45680 - 45687.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J L Nelson
Microchimerism and human autoimmune diseases
Lupus,
October 1, 2002;
11(10):
651 - 654.
[Abstract]
[PDF]
|
|
|
|
|
|
|
M. J. Cho, T. I. Pestina, S. A. Steward, C. A. Lowell, C. W. Jackson, and T. K. Gartner
Role of the Src family kinase Lyn in TxA2 production, adenosine diphosphate secretion, Akt phosphorylation, and irreversible aggregation in platelets stimulated with gamma -thrombin
Blood,
April 1, 2002;
99(7):
2442 - 2447.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Ishikawa, N. Tsuyama, S. Abroun, S. Liu, F.-J. Li, O. Taniguchi, and M. M. Kawano
Requirements of src family kinase activity associated with CD45 for myeloma cell proliferation by interleukin-6
Blood,
March 15, 2002;
99(6):
2172 - 2178.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Stafford, C. Lowell, S. Sur, and R. Alam
Lyn Tyrosine Kinase Is Important for IL-5-Stimulated Eosinophil Differentiation
J. Immunol.,
February 15, 2002;
168(4):
1978 - 1983.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Nijhuis, J.-W. J Lammers, L. Koenderman, and P. J. Coffer
Src kinases regulate PKB activation and modulate cytokine and chemoattractant-controlled neutrophil functioning
J. Leukoc. Biol.,
January 1, 2002;
71(1):
115 - 124.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Rodriguez, M. Matsuda, O. Perisic, J. Bravo, A. Paul, N. P. Jones, Y. Light, K. Swann, R. L. Williams, and M. Katan
Tyrosine Residues in Phospholipase Cgamma 2 Essential for the Enzyme Function in B-cell Signaling
J. Biol. Chem.,
December 14, 2001;
276(51):
47982 - 47992.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Kedzierska, N. J. Vardaxis, A. Jaworowski, and S. M. Crowe
Fc{gamma}R-mediated phagocytosis by human macrophages involves Hck, Syk, and Pyk2 and is augmented by GM-CSF
J. Leukoc. Biol.,
August 1, 2001;
70(2):
322 - 328.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. F. Vara, M. A. D. Caceres, A. Silva, and J. Martin-Perez
Src Family Kinases Are Required for Prolactin Induction of Cell Proliferation
Mol. Biol. Cell,
July 1, 2001;
12(7):
2171 - 2183.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. Tilbrook, G. A. Palmer, T. Bittorf, D. J. McCarthy, M. J. Wright, M. K. Sarna, D. Linnekin, V. S. Cull, J. H. Williams, E. Ingley, et al.
Maturation of Erythroid Cells and Erythroleukemia Development Are Affected by the Kinase Activity of Lyn
Cancer Res.,
March 1, 2001;
61(6):
2453 - 2458.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
H. Jiang, K. Foltenyi, M. Kashiwada, L. Donahue, B. Vuong, B. Hehn, and P. Rothman
Fes Mediates the IL-4 Activation of Insulin Receptor Substrate-2 and Cellular Proliferation
J. Immunol.,
February 15, 2001;
166(4):
2627 - 2634.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Hashimoto, K. Hirose, T. Kurosaki, and M. Iino
Negative Control of Store-Operated Ca2+ Influx by B Cell Receptor Cross-Linking
J. Immunol.,
January 15, 2001;
166(2):
1003 - 1008.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Stoiber, S. Stockinger, P. Steinlein, J. Kovarik, and T. Decker
Listeria monocytogenes Modulates Macrophage Cytokine Responses Through STAT Serine Phosphorylation and the Induction of Suppressor of Cytokine Signaling 3
J. Immunol.,
January 1, 2001;
166(1):
466 - 472.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Korade-Mirnics and S. J. Corey
Src kinase-mediated signaling in leukocytes
J. Leukoc. Biol.,
November 1, 2000;
68(5):
603 - 613.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
D. W. Lee, K. Zhang, Z.-Q. Ning, E. H. Raabe, S. Tintner, R. Wieland, B. J. Wilkins, J. M. Kim, R. I. Blough, and R. J. Arceci
Proliferation-associated SNF2-like Gene (PASG): A SNF2 Family Member Altered in Leukemia1
Cancer Res.,
July 1, 2000;
60(13):
3612 - 3622.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
P. J. Mansfield, J. A. Shayman, and L. A. Boxer
Regulation of polymorphonuclear leukocyte phagocytosis by myosin light chain kinase after activation of mitogen-activated protein kinase
Blood,
April 1, 2000;
95(7):
2407 - 2412.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Du, S. Tsai, J. R. Keller, and S. C. Williams
Identification of an Interleukin-3-regulated Aldoketo Reductase Gene in Myeloid Cells Which May Function in Autocrine Regulation of Myelopoiesis
J. Biol. Chem.,
March 15, 2000;
275(10):
6724 - 6732.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Munshi, J. E. Groopman, P. S. Gill, and R. K. Ganju
c-Src Mediates Mitogenic Signals and Associates with Cytoskeletal Proteins upon Vascular Endothelial Growth Factor Stimulation in Kaposi's Sarcoma Cells
J. Immunol.,
February 1, 2000;
164(3):
1169 - 1174.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Ping, J. Zhang, Y.-T. Zheng, R. C. X. Li, B. Dawn, X.-L. Tang, H. Takano, Z. Balafanova, and R. Bolli
Demonstration of Selective Protein Kinase C–Dependent Activation of Src and Lck Tyrosine Kinases During Ischemic Preconditioning in Conscious Rabbits
Circ. Res.,
September 17, 1999;
85(6):
542 - 550.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. C. Broudy, N. L. Lin, W. C. Liles, S. J. Corey, B. O'Laughlin, S. Mou, and D. Linnekin
Signaling via Src Family Kinases Is Required for Normal Internalization of the Receptor c-Kit
Blood,
September 15, 1999;
94(6):
1979 - 1986.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Stoiber, P. Kovarik, S. Cohney, J. A. Johnston, P. Steinlein, and T. Decker
Lipopolysaccharide Induces in Macrophages the Synthesis of the Suppressor of Cytokine Signaling 3 and Suppresses Signal Transduction in Response to the Activating Factor IFN-{gamma}
J. Immunol.,
September 1, 1999;
163(5):
2640 - 2647.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J L. NELSON
Non-host cells in the pathogenesis of autoimmune disease: a new paradigm?
Ann Rheum Dis,
September 1, 1999;
58(9):
518 - 520.
[Full Text]
|
|
|
|
|
|
|
J L Nelson
Microchimerism: implications for autoimmune disease
Lupus,
June 1, 1999;
8(5):
370 - 374.
[Abstract]
[PDF]
|
|
|
|
|
|
|
M. Sixt, R. Hallmann, O. Wendler, K. Scharffetter-Kochanek, and L. M. Sorokin
Cell Adhesion and Migration Properties of beta 2-Integrin Negative Polymorphonuclear Granulocytes on Defined Extracellular Matrix Molecules. RELEVANCE FOR LEUKOCYTE EXTRAVASATION
J. Biol. Chem.,
May 25, 2001;
276(22):
18878 - 18887.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Top
Hematopoiesis depends on growth...
The src family of...