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Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 4166-4176
Regulation and Function of WASp in Platelets by the Collagen Receptor,
Glycoprotein VI
Barbara S. Gross,
Jonathan I. Wilde,
Lynn Quek,
Helen Chapel,
David L. Nelson, and
Steve P. Watson
From the Department of Pharmacology, University of Oxford, Oxford,
UK; the Metabolism Branch, National Cancer Institute, National
Institutes of Health, Bethesda, MD; and the Department of Immunology,
John Radcliffe Hospital, Headington, Oxford, UK.
Wiskott Aldrich syndrome (WAS) is an X-linked recessive disorder
associated with abnormalities in platelets and lymphocytes giving rise
to thrombocytopenia and immunodeficiency. WAS is caused by a mutation
in the gene encoding the cytoskeletal protein (WASp). Despite its
importance, the role of WASp in platelet function is not established.
WASp was recently shown to undergo tyrosine phosphorylation in
platelets after activation by collagen, suggesting that it may play a
selective role in activation by the adhesion molecule. In the present
study, we show that WASp is heavily tyrosine phosphorylated by a
collagen-related peptide (CRP) that binds to the collagen receptor
glycoprotein (GP) VI, but not to the integrin  2 1.
Tyrosine phosphorylation of WASp was blocked by Src family kinase
inhibitors and reduced by treatment with wortmannin and in patients
with X-linked agammaglobulinemia (XLA), a condition caused by a lack of
functional expression of Btk. This indicates that Src kinases,
phosphatidylinositol 3-kinase (PI 3-kinase), and Btk all contribute to
the regulation of tyrosine phosphorylation of WASp. The functional
importance of WASp was investigated in 2 WAS brothers who show no
detectable expression of WASp. Platelet aggregation and secretion from
dense granules induced by CRP and thrombin was slightly enhanced in the
WAS platelets relative to controls. Furthermore, there was no apparent
difference in morphology in WAS platelets after stimulation by these
agonists. These observations suggest that WASp does not play a critical
role in intracellular signaling downstream of tyrosine kinase-linked
and G protein-coupled receptors in platelets.
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