Inhibition of antigen-receptor signaling by platelet endothelial cell adhesion molecule-1 (CD31) requires functional ITIMs, SHP-2, and p56lck
Inhibition of antigen-receptor signaling by platelet endothelial cell adhesion molecule-1 (CD31) requires functional ITIMs, SHP-2, and p56lck
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DOI：
10.1182/blood.v97.8.2351
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发表时间：
2001-04-15
期刊：
影响因子：
20.3
通讯作者：
Newman, PJ
中科院分区：
文献类型：
--
作者：
Newman, DK;Hamilton, C;Newman, PJ
血小板内皮细胞粘附分子-1（PECAM-1，CD 31）是免疫球蛋白基因超家族的一个130-kd成员，表达于血小板、内皮细胞、骨髓细胞和某些淋巴细胞亚群的表面。最近已经显示PECAM-1在其胞质结构域内含有功能性免疫受体酪氨酸基抑制基序（ITIM），并且PECAM-1与T细胞抗原受体（TCR）的共连接导致PECAM-1的酪氨酸磷酸化、含有Src同源2结构域的蛋白酪氨酸磷酸酶-2（SHP-2）的募集和TCR介导的细胞信号传导的减弱。为了确定淋巴细胞中PECAM-1抑制性信号传导的分子基础，该研究试图（1）确定PECAM-1 ITIM对其抑制活性的重要性，（2）确定SHP-2与SHP-1在介导PECAM-1抑制作用中的相对重要性，以及（3）鉴定T细胞中PECAM-1酪氨酸磷酸化所需的蛋白酪氨酸激酶。野生型PECAM-1与鸡DT 40 B细胞上表达的B细胞抗原受体的共连接导致钙动员的显著减少-类似于先前在T细胞中的观察结果。相比之下，无ITIM形式的PECAM-1的共连接没有抑制作用。此外，野生型PECAM-1不能减弱SHP-2缺陷型DT 40变体中的钙动员，尽管这些细胞中存在丰富水平的SHP-1。最后，PECAM-1在p56（lck）缺陷型Jurkat T细胞中未能变得酪氨酸磷酸化。总之，这些数据为PECAM-1调节抗原受体信号传导的分子要求提供了重要的见解。（Blood，2001; 97：2351-2357）（C）2001年由美国血液学学会。
Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1,CD31) is a 130-kd member of the immunoglobulin gene superfamily that is expressed on the surface of platelets, endothelial cells, myeloid cells, and certain lymphocyte subsets. PECAM-1 has recently been shown to contain functional immunoreceptor tyrosine-based inhibitory motifs (ITIMs) within its cytoplasmic domain, and co-ligation of PECAM-1 with the T-cell antigen receptor (TCR) results in tyrosine phosphorylation of PECAM-1, recruitment of Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2), and attenuation of TCR-mediated cellular signaling. To determine the molecular basis of PECAM-1 inhibitory signaling in lymphocytes, the study sought to (1) establish the importance of the PECAM-1 ITIMs for its inhibitory activity, (2) determine the relative importance of SHP-2 versus SHP-1 in mediating the inhibitory effect of PECAM-1, and (3) identify the protein tyrosine kinases required for PECAM-1 tyrosine phosphorylation in T cells. Co-ligation of wild-type PECAM-1 with the B-cell antigen receptor expressed on chicken DT40 B cells resulted in a marked reduction of calcium mobilization-similar to previous observations in T cells. In contrast, co-ligation of an ITIM-less form of PECAM-1 had no inhibitory effect. Furthermore, wild-type PECAM-1 was unable to attenuate calcium mobilization in SHP-2-deficient DT40 Variants despite abundant levels of SHP-1 in these cells. Finally, PECAM-1 failed to become tyrosine phosphorylated in p56(lck)-deficient Jurkat T cells. Together, these data provide important insights into the molecular requirements for PECAM-1 regulation of antigen receptor signaling. (Blood, 2001; 97:2351-2357) (C) 2001 by The American Society of Hematology.