PECAM-1 is involved in BCR/ABL signaling and may downregulate imatinib-induced apoptosis of Philadelphia chromosome-positive leukemia cells.
PECAM-1 is involved in BCR/ABL signaling and may downregulate imatinib-induced apoptosis of Philadelphia chromosome-positive leukemia cells.
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DOI：
10.3892/ijo.2012.1729
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发表时间：
2013-02
影响因子：
5.2
通讯作者：
Miura O
中科院分区：
文献类型：
--
作者：
Wu N;Kurosu T;Oshikawa G;Nagao T;Miura O
PECAM-1（CD 31）是一种基于免疫受体酪氨酸的抑制基序（ITIM）的表面糖蛋白，在各种造血细胞以及内皮细胞上表达。PECAM-1已被证明在调节粘附、迁移和凋亡中发挥作用。BCR/ABL融合酪氨酸激酶在慢性髓性白血病和费城阳性（Ph+）急性淋巴细胞白血病细胞中表达，临床上使用的酪氨酸激酶抑制剂伊马替尼或达沙替尼对其的抑制可诱导这些细胞的凋亡。在本研究中，我们证明PECAM-1是酪氨酸磷酸化的ITIM基序在各种BCR/ABL表达细胞，包括原代白血病细胞。使用伊马替尼和达沙替尼的研究以及在293 T细胞中的瞬时表达实验显示，PECAM-1被BCR/ABL直接磷酸化，这被伊马替尼抗性E255 K和T315 I突变增强，或部分被Src家族酪氨酸激酶，包括林恩，我们还通过使用SHP 2的底物捕获突变体证明，酪氨酸磷酸化的PECAM-1可以依赖于或独立于BCR/ABL被激活。1结合SHP 2，是BCR/ABL表达细胞中该酪氨酸磷酸酶的主要底物。PECAM-1在BCR/ABL表达细胞（包括K562人白血病细胞）中的过表达增强了细胞粘附，并部分抑制了伊马替尼诱导的细胞凋亡（涉及线粒体去极化和caspase-3裂解），至少部分是以ITIM非依赖性方式。这些数据表明，PECAM-1可能在调节细胞凋亡以及BCR/ABL表达细胞的粘附以调节其伊马替尼敏感性方面发挥作用，并且将是Ph+白血病治疗靶点的可能候选者。
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.
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