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Crkl is constitutively tyrosine phosphorylated in platelets from chronic
myelogenous leukemia patients and inducibly phosphorylated in normal
platelets stimulated by thrombopoietin
A Oda, Y Miyakawa, BJ Druker, A Ishida, K Ozaki, H Ohashi, M Wakui, M Handa, K Watanabe, S Okamoto and Y Ikeda
Department of Internal Medicine, Keio University, Tokyo, Japan.
Platelet functions such as aggregation and clot retraction are often
abnormal in chronic mylogenous leukemia (CML) patients. However, the
molecular mechanisms of these altered functions are unknown. As expression
of the p210bcr-abl oncogene product, a constitutively active tyrosine
kinase, is known to have an essential role in the pathogenesis of CML and
tyrosine phosphorylation is intimately involved in various aspects of
platelet activation, we examined the pattern of protein tyrosine
phosphorylation in platelets from 15 CML patients by immunoblotting with a
monoclonal antiphosphotyrosine antibody (4G10). Before and after
stimulation with thrombin, the only consistent difference between normal
and CML platelets was the presence of a tyrosine phosphorylated protein
with a relative molecular weight of 39 kD. This tyrosine phosphorylated
protein was identified as crid, an SH2, SH3 containing adapter protein.
Thus, as previously demonstrated for neutrophils from CML patients,
tyrosine phosphorylation of p39crkl persists in mature platelets. No
tyrosine phosphorylation of crid was detected following stimulation with
thrombin in normal platelets. However, crkl became incorporated into the
Triton X-100 insoluble residue following thrombin stimulation in a manner
dependent on platelet aggregation. Further, we found that crkl is an
endogenous substrate for calpain, a protease that may be involved in
postaggregation signaling processes. This suggests that crkl may be
involved in the reorganization of the cytoskeleton during normal platelet
aggregation and its tyrosine phosphorylation in CML platelets may
contribute to the abnormal platelet function in CML patients. Finally, we
found that thrombopoietin induces tyrosine phosphorylation of crk1 in
normal platelets and FDCP cells genetically engineered to express human
c-Mpl. This suggests that crk1 can be phosphorylated by a kinase other than
p210bcr-abl and that crk1 may have a role in signaling by thrombopoietin.
Volume 88,
Issue 11,
pp. 4304-4313,
12/01/1996
Copyright © 1996 by The American Society of Hematology
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