| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2010: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
|
|---|
| Research Abstract |
PECAM-1(CD31) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing surface glycoprotein expressed in various hematopoietic cells and plays roles in regulation of adhesion and migration of hematopoietic progenitor cells. PECAM-1 has also been implicated in activation of the Ras family GTPase Rap1 and in regulation of apoptosis. We previously reported that BCR/ABL activates the Rap1/B-Raf signaling pathway to regulate proliferation and integrin-mediated adhesion of Ph+ leukemic cells. In the present study, we demonstrate that PECAM-1 was tyrosine phosphorylated in ITIM in various BCR/ABL-expressing cells including primary CML and Ph+ ALL cells, which was inhibited by imatinib or dasatinib and was more prominently observed in cells expressing the imatinib-resistant E255K or T315I mutant. Transient expression experiments further revealed that ITIM in PECAM-1 was tyrosine phosphorylated by BCR/ABL or Lyn and was dephosphorylated by SHP2. Overexpression of PECAM-1 augmented BCR/ABL-mediated activation of Rap1/MEK/Erk pathway and enhanced chemotaxis induced by SDF-1, which also induced tyrosine phosphorylation of PECAM-1. Finally, PECAM-1 specifically inhibited apoptosis induced in K562 cells by imatinib or dasatinib but not that by the Bcl2 family antagonist ABT-737. These data suggest that PECAM-1 may play a role in regulation of apoptosis and migration of BCR/ABL-expressing cells to modulate their imatinib sensitivity and would be a possible candidate for therapeutic target in Ph+ leukemias.
|
