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Blood, Vol. 95 No. 1 (January 1), 2000:
pp. 19-29
REVIEW ARTICLE
From the Institute of Hematology, Erasmus University, Rotterdam, The
Netherlands; and the Institute of Life Science, Kurume University,
Japan.
The Janus kinase-signal transducer and
activator of transcription (Jak-Stat) pathway stands as a paradigm of
how diverse extracellular signals can elicit rapid changes in gene
expression in specific target cells. This pathway is widely used by
members of the cytokine receptor superfamily, including those for the
clinically important cytokines granulocyte colony-stimulating factor
(G-CSF), erythropoietin, thrombopoietin, the interferons, and numerous
interleukins, which makes it central to hematopoietic cell biology and
hematologic therapy alike. Indeed, study of the Jak-Stat pathway has
provided a wealth of information on hematopoiesis and hematopoietic
disease, and conversely, studies of hematopoietic disorders have
yielded new insights into the functions of Jaks and Stats. This review aims to detail the role of the Jak-Stat pathway in the normal development and function of hematopoietic cells and to describe how several hematopoietic disorders are caused, at least in part, by perturbations of this pathway.
Jaks are cytoplasmic tyrosine kinases that participate in signaling
from a range of cell-surface receptors, particularly members of the
cytokine receptor superfamily, which lack intrinsic tyrosine kinase
activity.1,2 There are 4 mammalian Jaks: Jak1, Jak2, Jak3,
and Tyk2. These associate with the weakly conserved "box 1" and
"box 2" recognition motifs in the membrane-proximal region of
cytokine receptors3,4 and are responsible for a range of
phosphorylation events on stimulation of such receptors with their
specific ligand. In addition, some receptors that have tyrosine kinase
activity, such as those for macrophage colony-stimulating factor and
stem cell factor, also activate Jaks, though it is unclear what role
they play in these instances.5,6
Stats are latent cytoplasmic transcription factors that become
activated after recruitment to an activated receptor complex. Subsequently, these active Stats translocate to the nucleus to affect
gene expression. Seven Stat proteins have been identified in mammalian
cells
A general model of Jak-Stat activation from cytokine receptors has
been proposed,2,21,41 though there are several exceptions and variations on the basic theme first elucidated for the interferon receptors.42 Binding of ligand to a cytokine receptor leads to the activation of Jaks, presumably through autophosphorylation on
tyrosines (Figure 1). Activated Jaks then
phosphorylate the receptor, creating docking sites for specific
signaling proteins, including Stat proteins, which the Jaks can then
phosphorylate on a conserved tyrosine residue at their C-terminus.
Subsequently, the Stats form stable homodimers and heterodimers by
interactions between the Src homology 2 (SH2) domain of one Stat
protein and the phosphotyrosine of another before translocation to the
nucleus, where they influence transcription of target genes by binding to specific regulatory sequences.21,41
Specificity in cytokine signaling is largely determined by the
combination of activated Jaks and Stats. A wide range of cytokines and
growth factors activate Jak1, Jak2, and Tyk, whereas Jak3 is only
activated by cytokines that have the common
The major function of Jaks is generally considered to be Stat
activation. However, this is clearly not the only role that Jaks play
in signaling. For example, Jaks are directly implicated in the
activation of the kinase Pyk2,74 stimulation of the
Ras-MAPK pathway,13,75,76 and the induction of the
c-fos and c-myc genes.77 Conversely, there
is considerable evidence that some activation of Stats occurs
independently of Jaks. For example, cell lines deficient in Jak2 or
Tyk2 showed no effect on G-CSF-dependent Stat activation, and a cell
line deficient in Jak1 showed only partial reduction in Stat3
activation.55 Similar results were obtained with
Jak knockout mice for a range of factors.16
Furthermore, Stat6 activation after CD40 engagement occurs
independently of detectable Jak phosphorylation.78 Such
data suggest that other kinases are probably also involved in mediating
Stat activation. In support of this, Src has been shown to bind and
activate Stat3 directly,79 whereas Bcr-Abl can also recruit
and activate Stat5 by the interaction of Stat5 with the adaptor CrkL,
which itself docks to Bcr-Abl.80 Other work implicates a
number of non-Jak kinases as responsible for the serine phosphorylation
of Stats.73,81
As further evidence of the importance of the Jak-Stat pathway,
negative feedback mechanisms have been identified that control its
activation (Table 4). These include
endosomal degradation of Jak/receptor complexes through
receptor-mediated endocytosis82,83 and the
dominant-negative effects of several naturally occurring Stat
variants.84,85 In addition, the PIAS proteins have been identified. They seem to bind directly to Stats and to inhibit DNA
binding, though their exact biologic role remains
unclear.72,86 Two other means of negative regulation, by
CIS/SOCS/SSI family members and by tyrosine phosphatases, have been
studied in more detail.
CIS/SOCS/SSI Family
Tyrosine phosphatases
The wide use of the Jak-Stat pathway by hematologically important
factors, the severity of artificially disrupting the Jak-Stat pathway
on hematopoiesis, and the number of key genes with Stat-response elements already provides some appreciation of the importance of this
pathway in hematopoiesis and the regulation of hematopoietic cell
function. We will now summarize the studies showing that several
diverse hematopoietic disorders exhibit perturbations in the Jak-Stat
pathway. Indeed, in a number of these cases, experiments have directly
implicated the altered Jak or Stat signaling, or both, in the
pathogenesis of the disease. Such molecular investigations provide a
foundation on which to build an understanding of these conditions and a
framework for rational improvements in therapy.
Aberrant activation of Jaks and Stats
Evidence for Jak-Stat involvement
Alterations in the Jak-Stat pathway have been associated either
directly or indirectly with other hematologic disease states.
Severe combined immunodeficiency
Severe congenital neutropenia/acute myeloid leukemia
Benign erythrocytosis Benign erythrocytosis is a dominant autosomal condition characterized by a mild increase in red blood cell counts and normal serum levels of erythropoietin because of hypersensitivity to erythropoietin.159,160 In addition, there is an increased and a sustained activation of Jak2 and Stat5 after erythropoietin stimulation.112,160 A number of pedigrees have been identified, all of which lead to erythropoietin (EPO)-R truncations161,162 that invariably result in the loss of the binding site for SHP-1 at Tyr 449 of the EPO-R.112 Because SHP-1 is a negative regulator of Jak2 activation by EPO, it appears that lack of SHP-1 activation is responsible for the altered Jak-Stat kinetics and enhanced EPO responses in these patients (Figure 3).Fanconi anemia Fanconi anemia (FA) is an autosomal recessive chromosome instability syndrome characterized by progressive bone marrow failure and an increased susceptibility to malignancy.163,164 The FA group C gene (FAC) has been identified, with its disruption leading to profound hypersensitivity of hematopoietic precursor cells to IFN-
in mice165 and in patients with FA group C.166
This appears to be the result of sustained Stat1 activation leading to
apoptosis of these cells.166 Other researchers have
reported that the FAC protein is involved in the recruitment of Stat1
to the IFN- receptor complex,167 which further suggests
that perturbed Stat1 activation contributes to the phenotype of this disease.
Interferon resistance Interferons, particularly IFN- , have important therapeutic
applications in the treatment of hematologic malignancies, including CML, hairy cell leukemia, and cutaneous T-cell lymphoma
(CTCL).168,169 However, the efficacy is limited by the
development of clinical resistance to IFN therapy in these
patients.169 Efforts to understand the molecular basis of
IFN resistance have been made by generating somatic cell mutants
resistant to IFN, which showed that defects in the IFN receptor, Jaks,
or Stats could contribute to this phenomenon.21,42 Similar
analysis of IFN--resistant derivatives of CTCL cells also revealed
a defect in normal Jak-Stat responses caused by a total absence of
Stat1 expression,170 as previously observed in patients
with IFN-resistant melanoma.171 However, a recent study
also suggests a possible role for JAB in IFN resistance, especially for
patients with a dominant phenotype.172 Stable expression of
JAB in either NIH-3T3 or M1 leukemic cells leads to resistance to
IFN-- and IFN- -induced growth arrest. In both cell systems,
IFN- did not induce tyrosine phosphorylation and DNA-binding
activity of Stat1. In addition, IFN-resistant clones derived from LoVo
cells and Daudi cells were found to express high endogenous levels of
JAB without stimulation, with a concomitant reduction in IFN-induced
Stat1 and Jak phosphorylation.172
Other diseases with altered Jak-Stat activation Other hematologic diseases also show defects in the normal activation and regulation of Jak-Stat pathway components. For example, bone marrow cells from patients with myelodysplastic syndrome show impaired erythropoietin-induced Stat5 activation,173 whereas reduced Tyk2/SHP-1 interaction has been observed in a kindred of familial hemophagocytic lymphohistiocytosis.174 However, additional experiments will be required to identify mechanisms by which these perturbations in the Jak-Stat pathway may contribute to the pathogenesis of disease.
It is clear from this review that the Jak-Stat pathway is perturbed in a variety of malignancies and hematopoietic disorders. There is also now solid evidence that constitutive activation of Jak-Stat pathway components plays an important role in transformation by Tel-Jak, Bcr-Abl, and v-Src and in multiple myeloma. Furthermore, the importance of defective Jak3 activation in SCID and of extended Stat5 activation in the hyperproliferative responses of truncated G-CSF-R is now established. However, the significance of altered Jak-Stat activation in the other disorders remains less clear. In each case, the judicious expression of dominant-negative or constitutively active Jak-Stat pathway components in either cell line or mouse models of these disorders should enable the relative contribution of altered Jak-Stat signaling to the disease phenotype to be established. In addition, the availability of numerous mouse strains either deficient or transgenic for specific Jak-Stat components provides additional opportunity for assessing their importance in vivo.
Much remains to be learned about structure/function relationships of Jaks and Stats and about the cross talk between the Jak-Stat pathway and other signaling pathways in hematopoietic cells. In addition, as outlined above, the definitive roles played by Stats in growth control and transformation must be determined. Furthermore, a complete understanding of the mechanisms by which the Jak-Stat pathway is negatively regulated remains an important goal. However, there is already much promise in applying the knowledge obtained on the Jak-Stat pathway and its perturbation for the development of innovative hematologic treatment strategies. As mentioned above, specific Jak inhibitors may have important clinical applications in acute lymphoblastic leukemia,128 and there is clear potential for using gene therapy to remedy Jak3 deficiency in SCID.175,176 Recent data providing the crystallographic structure of Stat1 and Stat3 complexed with DNA177,178 opens the way for a finer understanding of Stat specificity at the molecular level, increasing the knowledge base required for designing suitable compounds for pharmacologic intervention. It is anticipated that future developments will further facilitate the translation of the basic science of the Jak-Stat pathway into the hematology clinic.
The authors apologize to colleagues whose works were not cited because of the size restrictions of the review.
Submitted May 3 1999; accepted August 6, 1999.
Supported by an EMBO Long Term Fellowship and the NWO (A.C.W.) and by grants from the Ministry of Science, Education and Culture of Japan, the TORAY Research Foundation, and the Uehara Memorial Research Foundation (A.Y.).
Reprints: Alister C. Ward, Institute of Hematology, Erasmus University Rotterdam, P. O. Box 1738, 3000 DR Rotterdam, Netherlands; e-mail: ward{at}hema.fgg.eur.nl.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
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 S.-H. Jung, C. J. Evans, C. Uemura, and U. Banerjee The Drosophila lymph gland as a developmental model of hematopoiesis Development, June 1, 2005; 132(11): 2521 - 2533. [Abstract] [Full Text] [PDF]
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 F. Farrell and A. Lee The Erythropoietin Receptor and Its Expression in Tumor Cells and Other Tissues Oncologist, November 1, 2004; 9(suppl_5): 18 - 30. [Abstract] [Full Text] [PDF]
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C.-S. Chim, T.-K. Fung, W.-C. Cheung, R. Liang, and Y.-L. Kwong SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway Blood, June 15, 2004; 103(12): 4630 - 4635. [Abstract] [Full Text] [PDF]
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L. Gate, R. S. Majumdar, A. Lunk, and K. D. Tew Increased Myeloproliferation in Glutathione S-Transferase {pi}-deficient Mice Is Associated with a Deregulation of JNK and Janus Kinase/STAT Pathways J. Biol. Chem., March 5, 2004; 279(10): 8608 - 8616. [Abstract] [Full Text] [PDF]
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 R. P. Sorrentino, J. P. Melk, and S. Govind Genetic Analysis of Contributions of Dorsal Group and JAK-Stat92E Pathway Genes to Larval Hemocyte Concentration and the Egg Encapsulation Response in Drosophila Genetics, March 1, 2004; 166(3): 1343 - 1356. [Abstract] [Full Text] [PDF]
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 C.-H. Shen and L. A. Steiner Genome Structure and Thymic Expression of an Endogenous Retrovirus in Zebrafish J. Virol., January 15, 2004; 78(2): 899 - 911. [Abstract] [Full Text] [PDF]
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R. K. H. Lo, H. Cheung, and Y. H. Wong Constitutively Active G{alpha}16 Stimulates STAT3 via a c-Src/JAK- and ERK-dependent Mechanism J. Biol. Chem., December 26, 2003; 278(52): 52154 - 52165. [Abstract] [Full Text] [PDF]
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S. Ilangumaran, D. Finan, J. Raine, and R. Rottapel Suppressor of Cytokine Signaling 1 Regulates an Endogenous Inhibitor of a Mast Cell Protease J. Biol. Chem., October 24, 2003; 278(43): 41871 - 41880. [Abstract] [Full Text] [PDF]
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B. Jones, S. Adams, G. T. Miller, M. I. Jesson, T. Watanabe, and B. P. Wallner Hematopoietic stimulation by a dipeptidyl peptidase inhibitor reveals a novel regulatory mechanism and therapeutic treatment for blood cell deficiencies Blood, September 1, 2003; 102(5): 1641 - 1648. [Abstract] [Full Text] [PDF]
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 I. Ben-Shlomo, S. Yu Hsu, R. Rauch, H. W. Kowalski, and A. J. W. Hsueh Signaling Receptome: A Genomic and Evolutionary Perspective of Plasma Membrane Receptors Involved in Signal Transduction Sci. Signal., June 17, 2003; 2003(187): re9 - re9. [Abstract] [Full Text] [PDF]
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O. Galm, H. Yoshikawa, M. Esteller, R. Osieka, and J. G. Herman SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma Blood, April 1, 2003; 101(7): 2784 - 2788. [Abstract] [Full Text] [PDF]
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 J. J. Kohler, D. L. Tuttle, C. R. Coberley, J. W. Sleasman, and M. M. Goodenow Human immunodeficiency virus type 1 (HIV-1) induces activation of multiple STATs in CD4+ cells of lymphocyte or monocyte/macrophage lineages J. Leukoc. Biol., March 1, 2003; 73(3): 407 - 416. [Abstract] [Full Text] [PDF]
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 F. Ravandi, M. Talpaz, and Z. Estrov Modulation of Cellular Signaling Pathways: Prospects for Targeted Therapy in Hematological Malignancies Clin. Cancer Res., February 1, 2003; 9(2): 535 - 550. [Abstract] [Full Text] [PDF]
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K. A. Johansen, D. D. Iwaki, and J. A. Lengyel Localized JAK/STAT signaling is required for oriented cell rearrangement in a tubular epithelium Development, January 1, 2003; 130(1): 135 - 145. [Abstract] [Full Text] [PDF]
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J. ten Hoeve, M. de Jesus Ibarra-Sanchez, Y. Fu, W. Zhu, M. Tremblay, M. David, and K. Shuai Identification of a Nuclear Stat1 Protein Tyrosine Phosphatase Mol. Cell. Biol., August 15, 2002; 22(16): 5662 - 5668. [Abstract] [Full Text] [PDF]
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T. Hayashi, T. Hideshima, M. Akiyama, P. Richardson, R. L. Schlossman, D. Chauhan, N. C. Munshi, S. Waxman, and K. C. Anderson Arsenic Trioxide Inhibits Growth of Human Multiple Myeloma Cells in the Bone Marrow Microenvironment Mol. Cancer Ther., August 1, 2002; 1(10): 851 - 860. [Abstract] [Full Text] [PDF]
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M. Nikolova, P. Musette, M. Bagot, L. Boumsell, and A. Bensussan Engagement of ILT2/CD85j in Sezary syndrome cells inhibits their CD3/TCR signaling Blood, July 18, 2002; 100(3): 1019 - 1025. [Abstract] [Full Text] [PDF]
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 I. C. Haznedaroglu, H. Goker, M. Turgut, Y. Buyukasik, and M. Benekli Thrombopoietin as a Drug: Biologic Expectations, Clinical Realities, and Future Directions Clinical and Applied Thrombosis/Hemostasis, July 1, 2002; 8(3): 193 - 212. [Abstract] [PDF]
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 L. Velazquez, A. M. Cheng, H. E. Fleming, C. Furlonger, S. Vesely, A. Bernstein, C. J. Paige, and T. Pawson Cytokine Signaling and Hematopoietic Homeostasis Are Disrupted in Lnk-deficient Mice J. Exp. Med., June 17, 2002; 195(12): 1599 - 1611. [Abstract] [Full Text] [PDF]
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M. Nieborowska-Skorska, G. Hoser, P. Kossev, M. A. Wasik, and T. Skorski Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis Blood, May 29, 2002; 99(12): 4531 - 4539. [Abstract] [Full Text] [PDF]
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C. Wuchter, V. Ruppert, M. Schrappe, B. Dorken, W.-D. Ludwig, and L. Karawajew In vitro susceptibility to dexamethasone- and doxorubicin-induced apoptotic cell death in context of maturation stage, responsiveness to interleukin 7, and early cytoreduction in vivo in childhood T-cell acute lymphoblastic leukemia Blood, May 13, 2002; 99(11): 4109 - 4115. [Abstract] [Full Text] [PDF]
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J. W. Snow, N. Abraham, M. C. Ma, N. W. Abbey, B. Herndier, and M. A. Goldsmith STAT5 promotes multilineage hematolymphoid development in vivo through effects on early hematopoietic progenitor cells Blood, January 1, 2002; 99(1): 95 - 101. [Abstract] [Full Text] [PDF]
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M. Benekli, Z. Xia, K. A. Donohue, L. A. Ford, L. A. Pixley, M. R. Baer, H. Baumann, and M. Wetzler Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival Blood, January 1, 2002; 99(1): 252 - 257. [Abstract] [Full Text] [PDF]
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T.-S. Migone, M. Humbert, A. Rascle, D. Sanden, A. D'Andrea, and J. A. Johnston The deubiquitinating enzyme DUB-2 prolongs cytokine-induced signal transducers and activators of transcription activation and suppresses apoptosis following cytokine withdrawal Blood, September 15, 2001; 98(6): 1935 - 1941. [Abstract] [Full Text] [PDF]
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X.-F. Zhang, J.-F. Wang, E. Matczak, J. Proper, and J. E. Groopman Janus kinase 2 is involved in stromal cell-derived factor-1{alpha}-induced tyrosine phosphorylation of focal adhesion proteins and migration of hematopoietic progenitor cells Blood, June 1, 2001; 97(11): 3342 - 3348. [Abstract] [Full Text] [PDF]
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R. F. Duarte and D. A. Frank SCF and G-CSF lead to the synergistic induction of proliferation and gene expression through complementary signaling pathways Blood, November 15, 2000; 96(10): 3422 - 3430. [Abstract] [Full Text] [PDF]
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 S. A. K. Merediz, M. Schmidt, G. J. Hoppe, J. Alfken, D. Meraro, B.-Z. Levi, A. Neubauer, and B. Wittig Cloning of an interferon regulatory factor 2 isoform with different regulatory ability Nucleic Acids Res., November 1, 2000; 28(21): 4219 - 4224. [Abstract] [Full Text] [PDF]
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P. W. Zandstra, D. A. Lauffenburger, and C. J. Eaves A ligand-receptor signaling threshold model of stem cell differentiation control: a biologically conserved mechanism applicable to hematopoiesis Blood, August 15, 2000; 96(4): 1215 - 1222. [Abstract] [Full Text] [PDF]
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A. Kusch, S. Tkachuk, H. Haller, R. Dietz, D. C. Gulba, M. Lipp, and I. Dumler Urokinase Stimulates Human Vascular Smooth Muscle Cell Migration via a Phosphatidylinositol 3-Kinase-Tyk2 Interaction J. Biol. Chem., December 8, 2000; 275(50): 39466 - 39473. [Abstract] [Full Text] [PDF]
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J. Du, Y. M. Alsayed, F. Xin, S. J. Ackerman, and L. C. Platanias Engagement of the CrkL Adapter in Interleukin-5 Signaling in Eosinophils J. Biol. Chem., October 13, 2000; 275(42): 33167 - 33175. [Abstract] [Full Text] [PDF]
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Top
Introduction
Jaks
Stats1 to 6, including Stat5a and Stat5b, which are encoded by
distinct genes. In addition, different isoforms of several Stats have
been identified.
