|
|
 Previous Article | Table of Contents | Next Article 
Abnormal inside-out signal transduction-dependent activation of
glycoprotein IIb-IIIa in a patient with impaired pleckstrin phosphorylation
J Gabbeta, X Yang, L Sun, MA McLane, S Niewiarowski and AK Rao
Sol Sherry Thrombosis Research Center, Philadelphia, PA, USA.
Platelet-agonist interaction results in activation of glycoprotein (GP)
IIb-IIIa complex and fibrinogen binding, a prerequisite for platelet
aggregation. Fibrinogen binding exposes new antibody binding sites on
GPIIb-IIIa (ligand-induced binding sites: LIBS). Signal transduction
events, including pleckstrin phosphorylation by protein kinase C (PKC), are
considered to regulate GPIIb-IIIa activation. We studied a 16-year- old
white male with lifelong mucocutaneous bleeding manifestations and abnormal
platelet aggregation and secretion in response to multiple agonists.
Pleckstrin phosphorylation was diminished in response to
platelet-activating factor (PAF; 4 and 400 nmol/L) and thrombin (0.05
U/mL). Binding of monoclonal antibodies (MoAbs) 10E5 and A2A9, which bind
to both resting and activated GPIIb-IIIa, was normal. Binding of MoAb PAC1,
which binds to only activated GPIIb-IIIa, was diminished upon activation
with PAF, adenosine diphosphate (ADP), thrombin receptor agonist peptide
(SFLLRN), A23187, and 1,2-dioctonylglycerol (DiC8). Signal
transduction-dependent LIBS expression (studied using MoAb 62) induced by
ADP, SFLLRN, and DiC8 and signal transduction- independent LIBS expression
induced by RGDS peptide or disintegrin albolabrin were normal or minimally
decreased, indicating the presence of intact ligand binding sites. We
conclude that the patient's platelets have a defect in inside-out signal
transduction-dependent GPIIb-IIIa activation due to an upstream defect in
the signal transduction mechanisms rather than in the GPIIb-IIIa complex
itself. Our findings extend the spectrum of congenital mechanisms leading
to impaired aggregation from defects in GPIIb-IIIa per se to aberrations in
signaling mechanisms.
Volume 87,
Issue 4,
pp. 1368-1376,
02/15/1996
Copyright © 1996 by The American Society of Hematology
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
G. S Jalagadugula, G. Kaur, G. Mao, D. Dhanasekaran, and A. K. Rao
RUNX1/CBFA2 Regulates Myosin Light Chain 9 (MYL9) in Megakaryocytic Cells: Decreased MYL9 Expression in Human RUNX1 Haplodeficiency.
Blood (ASH Annual Meeting Abstracts),
November 16, 2008;
112(11):
1831 - 1831.
[Abstract]
|
|
|
|
|
|
|
A. K. Rao
Decreased platelet Mpl receptor in AML1 haplodeficiency: another piece of the puzzle
Blood,
June 15, 2005;
105(12):
4545 - 4545.
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Sun, J. R. Gorospe, E. P. Hoffman, and A. K. Rao
Decreased Platelet Expression of MYL9 (Myosin Regulatory Light Chain Polypeptide) and Other Genes with Platelets Dysfunction and CBFA2 Mutation: Insights from Platelet Expression Profiling.
Blood (ASH Annual Meeting Abstracts),
November 16, 2004;
104(11):
737 - 737.
[Abstract]
|
|
|
|
|
|
|
L. Sun, G. Mao, and A. K. Rao
Association of CBFA2 mutation with decreased platelet PKC-{theta} and impaired receptor-mediated activation of GPIIb-IIIa and pleckstrin phosphorylation: proteins regulated by CBFA2 play a role in GPIIb-IIIa activation
Blood,
February 1, 2004;
103(3):
948 - 954.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. L. Reed, M. L. Fitzgerald, and J. Polgar
Molecular mechanisms of platelet exocytosis: insights into the "secrete" life of thrombocytes
Blood,
November 15, 2000;
96(10):
3334 - 3342.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. K. Rao and J. Gabbeta
Congenital Disorders of Platelet Signal Transduction
Arterioscler Thromb Vasc Biol,
February 1, 2000;
20(2):
285 - 289.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Shiraga, Y. Tomiyama, S. Honda, H. Suzuki, S. Kosugi, S. Tadokoro, Y. Kanakura, K. Tanoue, Y. Kurata, and Y. Matsuzawa
Involvement of Na+/Ca2+ Exchanger in Inside-Out Signaling Through the Platelet Integrin alpha IIbbeta 3
Blood,
November 15, 1998;
92(10):
3710 - 3720.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. J. Shattil, H. Kashiwagi, and N. Pampori
Integrin Signaling: The Platelet Paradigm
Blood,
April 15, 1998;
91(8):
2645 - 2657.
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Hers, J. Donath, G. van Willigen, and J. W. N. Akkerman
Differential Involvement of Tyrosine and Serine/Threonine Kinases in Platelet Integrin {alpha}IIbß3 Exposure
Arterioscler Thromb Vasc Biol,
March 1, 1998;
18(3):
404 - 414.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Gabbeta, X. Yang, M. A. Kowalska, L. Sun, N. Dhanasekaran, and A. K. Rao
Platelet signal transduction defect with Galpha subunit dysfunction and diminished Galpha q in a patient with abnormal platelet responses
PNAS,
August 5, 1997;
94(16):
8750 - 8755.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Kienzle, S. Cross, D. B. Young, I. Misko, T. B. Sculley, and C. S. Abrams
Evidence That the Expression and Phosphorylation Status of Pleckstrin Is Modulated by Epstein-Barr Virus in Human B Lymphocytes
Blood,
May 1, 1997;
89(9):
3488 - 3489.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. Hartwig, S. Kung, T. Kovacsovics, P. A. Janmey, L. C. Cantley, T. P. Stossel, and A. Toker
D3 Phosphoinositides and Outside-in integrin Signaling by Glycoprotein IIb-IIIa Mediate Platelet Actin Assembly and Filopodial Extension Induced by Phorbol 12-Myristate 13-Acetate
J. Biol. Chem.,
December 20, 1996;
271(51):
32986 - 32993.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
