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p120c-cbl is present in human blood platelets and is differentially
involved in signaling by thrombopoietin and thrombin
A Oda, K Ozaki, BJ Druker, Y Miyakawa, H Miyazaki, M Handa, H Morita, H Ohashi and Y Ikeda
Department of Internal Medicine, Keio University, Tokyo, Japan.
To investigate the signaling processes induced by recombinant
thrombopoietin, we used human platelets to recently show that
thrombopoietin induces rapid tyrosine phosphorylation of Jak2, Tyk2, Shc,
Stat3, Stat5, and other proteins in human platelets. Because the apparent
molecular weight of a major tyrosine-phosphorylated protein in platelets
stimulated by thrombopoietin is approximately 120 kD, we examined the
possibility that this could be p120c-cbl, a protein known to be involved in
signaling by many growth factors. Specific antisera against p120c-cbl
recognized the same 120-kD protein in lysates of Jurkat cells, which are
known to express p120c-cbl, and platelets, indicating that platelets have
p120c-cbl. Thrombopoietin induced rapid tyrosine phosphorylation of
p120c-cbl in platelets. Thrombopoietin also induced tyrosine
phosphorylation of p120c-cbl in FDCP cells genetically engineered to
express the thrombopoietin receptor, c-Mpl. Interestingly, FDCP cells,
expressing a truncated c-Mpl devoid of the box-2 domain, proliferate in
response to thrombopoietin. However, no increase in tyrosine
phosphorylation of p120c-cbl was observed upon treatment of these cells
with thrombopoietin, indicating that in this system tyrosine
phosphorylation of p120c-cbl may not be essential for cell proliferation.
This suggests that tyrosine phosphorylation of p120c-cbl may be required
for nonmitogenic responses induced by thrombopoietin in postmitotic cells
such as platelets. On the other hand, p120c-cbl was not significantly
tyrosine-phosphorylated upon treatment of platelets with thrombin. However,
it became incorporated into the Triton X-100-insoluble,
10,000g-sedimentable residue in an aggregation-dependent manner, suggesting
that it may have a regulatory role in platelet cytoskeletal processes.
p120c-cbl was constitutively associated with a 28-kD adapter protein, Grb2,
that was also incorporated into the Triton X-100-insoluble, sedimentable
residue dependent on aggregation. Further, we found that p120c-cbl is an
endogenous substrate for calpain, a protease that may play a role in
postaggregation signaling processes. Our data suggest that p120c-cbl may be
involved in signal transduction following ligand binding to c- Mpl through
its inducible tyrosine phosphorylation, and it may also be involved in
signaling during platelet aggregation by its redistribution to the
cytoskeleton.
Volume 88,
Issue 4,
pp. 1330-1338,
08/15/1996
Copyright © 1996 by The American Society of Hematology
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