title: PECAM-1 is involved in BCR/ABL signaling and may downregulate imatinib-induced             apoptosis of Philadelphia chromosome-positive leukemia cells.
abstract: 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.
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental                     Sciences, Tokyo Medical and Dental University, Bunkyoku, Tokyo 113-8519,                     Japan.
authors.forename: Nan
authors.initials: N
authors.lastname: Wu
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kurosu
authors.forename: Gaku
authors.initials: G
authors.lastname: Oshikawa
authors.forename: Toshikage
authors.initials: T
authors.lastname: Nagao
authors.forename: Osamu
authors.initials: O
authors.lastname: Miura
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000494:pharmacology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001549:Benzamides; D010879:Piperazines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl