| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1999: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Research Abstract |
Erythropoietin (Epo) is a hematopoietic growth factor that regulates the growth and differentiation of erythroid progenitor cells through activation of its specific receptor expressed on the cell surface. The receptor for Epo (EpoR) transduces its signals by activating receptor-associated tyrosine kinases, mainly Jak2 and Lyn, and thereby inducing tyrosine phosphorylation of various signaling molecules including the EpoR itself. We have found that CrkL, an adapter protein implicated in pathogenesis of chronic myelogenous leukemia, is recruited to the EpoR, possibly through interaction between the CrkL SH2 domain and phosphorylated Y-460 in the EpoR cytoplasmic domain, and undergoes tyrosine phosphorylation by receptor-associated Lyn in Epo-stimulated hematopoietic cells. Through its interaction with C3G, a guanine nucleotide exchange factor for the Ras family GTPases, CrkL was found to mediate Epo-induced activation of Ras and Rap1. By using various mutants of these GTPases and other signaling molecules, we have also found that the activation of Rap1 is involved in stimulation of VLA-4 and VLA-5 integrin-mediated adhesion of hematopoietic cells. It was further indicated that phospholipase C-g, known to be activated by the EpoR, may also mediate the Epo-induced Rap1 activation through generation of its second messengers. Together, these data indicate that the EpoR activates Rap1 through recruitment of the CrkL/C3G complex as well as through activation of phospholipase C-g, which results in activation of integrin-mediated hematopoietic cell adhesion.
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