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Thrombopoietin and thrombin induce tyrosine phosphorylation of Vav in human
blood platelets
Y Miyakawa, A Oda, BJ Druker, K Ozaki, M Handa, H Ohashi and Y Ikeda
Department of Internal Medicine and Blood Center, Keio University,
Shinjuku-ku, Tokyo, Japan.
Thrombopoietin has an essential role in megakaryopoiesis and
thrombopoiesis. To investigate the signaling processes induced by
thrombopoietin, we have employed human platelets and recently demonstrated
that thrombopoietin induces rapid tyrosine phosphorylation of Jak-2, Tyk2,
Shc, Stat3, Stat5, p120(c-cbl) and other proteins in human platelets.
Because the apparent molecular weight of a major tyrosine phosphorylated
protein in platelets stimulated by thrombopoietin is approximately 85 to 95
kD, we examined the possibility that this could be Vav, a 95-kD
proto-oncogene product. Specific antisera against Vav recognized the same
95 kD protein in lysates of Jurkat cells, which are known to express Vav,
and platelets, indicating that platelets have Vav. Thrombopoietin induced
rapid tyrosine phosphorylation of Vav in platelets without an elevation in
cytosolic free calcium concentration or activation of protein kinase C. Vav
was also tyrosine phosphorylated upon treatment of platelets with thrombin,
collagen, or U46619, which activate phospholipase C, leading to an
increased ionized calcium concentration and activation of protein kinase C.
Ionomycin or phorbol 12-myristate 13-acetate (PMA) also induces tyrosine
phosphorylation of Vav, suggesting that an increase in ionized calcium
concentration or activation of protein kinase C may lead to phosphorylation
of Vav. Thrombopoietin also induced tyrosine phosphorylation of Vav in
FDCP-2 cells, genetically engineered to express human c-Mpl (FDCP-hMpl5).
However, neither ionomycin nor PMA induced an increase in tyrosine
phosphorylation of Vav in FDCP-hMpl5 cells, suggesting that the calcium and
protein kinase C pathways of Vav phosphorylation may be unique to
platelets. Further, Vav became incorporated into the Triton X-100 insoluble
10,000 g sedimentable residue in an aggregation-dependent manner,
suggesting that it may have a regulatory role in platelet cytoskeletal
processes. Vav was constitutively associated with a 28-kD adapter protein,
Grb2, which is also incorporated into the cytoskeleton in an
aggregation-dependent fashion. Lastly, we found that Vav is cleaved when
there is activation of calpain, a protease that may have a role in
postaggregation signaling processes. Our data suggest that thrombopoietin
and other agonists may induce tyrosine phosphorylation of Vav by different
mechanisms and Vav may also be involved in signaling during platelet
aggregation by its redistribution to the cytoskeleton.
Volume 89,
Issue 8,
pp. 2789-2798,
04/15/1997
Copyright © 1997 by The American Society of Hematology
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