PECAM-1 (CD31) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing             surface glycoprotein expressed on various hematopoietic cells as well as on endothelial             cells. PECAM-1 has been shown to play roles in regulation of adhesion, migration             and apoptosis. The BCR/ABL fusion tyrosine kinase is expressed in chronic myeloid             leukemia and Philadelphia-positive (Ph+) acute lymphoblastic leukemia cells, and             its inhibition by the clinically used tyrosine kinase inhibitors imatinib or dasatinib             induces apoptosis of these cells. In the present study, we demonstrate that PECAM-1             is tyrosine phospho-rylated in its ITIM motifs in various BCR/ABL-expressing cells             including primary leukemia cells. Studies using imatinib and dasatinib as well             as transient expression experiments in 293T cells revealed that PECAM-1 was phosphorylated             directly by BCR/ABL, which was enhanced by the imatinib-resistant E255K and T315I             mutations, or partly by the Src family tyrosine kinases, including Lyn, which             were activated dependently or independently on BCR/ABL. We also demonstrate by             using a substrate trapping mutant of SHP2 that tyrosine phosphorylated PECAM-1             binds SHP2 and is a major substrate for this tyrosine phosphatase in BCR/ABL-expressing             cells. Overexpression of PECAM-1 in BCR/ABL-expressing cells, including K562 human             leukemia cells, enhanced cell adhesion and partially inhibited imatinib-induced             apoptosis involving mitochondria depolarization and caspase-3 cleavage, at least             partly, in an ITIM-independent manner. These data suggest that PECAM-1 may play             a role in regulation of apoptosis as well as adhesion of BCR/ABL-expressing cells             to modulate their imatinib sensitivity and would be a possible candidate for therapeutic             target in Ph+ leukemias.
PECAM-1 ( CD31 ) is an immunoreceptor tyrosine - based inhibitory motif ( ITIM)-containing surface glycoprotein expressed on various hematopoietic cells as well as on endothelial cells . PECAM-1 has been shown to play roles in regulation of adhesion , migration and apoptosis . The BCR / ABL fusion tyrosine kinase is expressed in chronic myeloid leukemia and Philadelphia - positive ( Ph+ ) acute lymphoblastic leukemia cells , and its inhibition by the clinically used tyrosine kinase inhibitors imatinib or dasatinib induces apoptosis of these cells . In the present study , we demonstrate that PECAM-1 is tyrosine phospho - rylated in its ITIM motifs in various BCR / ABL - expressing cells including primary leukemia cells . Studies using imatinib and dasatinib as well as transient expression experiments in 293 T cells revealed that PECAM-1 was phosphorylated directly by BCR / ABL , which was enhanced by the imatinib - resistant E255 K and T315I mutations , or partly by the Src family tyrosine kinases , including Lyn , which were activated dependently or independently on BCR / ABL . We also demonstrate by using a substrate trapping mutant of SHP2 that tyrosine phosphorylated PECAM-1 binds SHP2 and is a major substrate for this tyrosine phosphatase in BCR / ABL - expressing cells . Overexpression of PECAM-1 in BCR / ABL - expressing cells , including K562 human leukemia cells , enhanced cell adhesion and partially inhibited imatinib - induced apoptosis involving mitochondria depolarization and caspase-3 cleavage , at least partly , in an ITIM - independent manner . These data suggest that PECAM-1 may play a role in regulation of apoptosis as well as adhesion of BCR / ABL - expressing cells to modulate their imatinib sensitivity and would be a possible candidate for therapeutic target in Ph+ leukemias .
What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?
What tyrosine kinase , involved in a Philadelphia- chromosome positive chronic myelogenous leukemia , is the target of Imatinib ( Gleevec ) ?
BCR-ABL
BCR-ABL