Newman D K, Hamilton C, Newman P J
Blood Research Institute, The Blood Center of Southeastern Wisconsin, Milwaukee, WI 53233, USA.
Blood. 2001 Apr 15;97(8):2351-7. doi: 10.1182/blood.v97.8.2351.
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.
血小板内皮细胞黏附分子-1（PECAM-1，CD31）是免疫球蛋白基因超家族的一个130千道尔顿成员，表达于血小板、内皮细胞、髓样细胞及某些淋巴细胞亚群的表面。最近研究表明，PECAM-1在其胞质结构域中含有功能性基于免疫受体酪氨酸的抑制基序（ITIMs），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Src同源2结构域的蛋白酪氨酸磷酸酶-2（SHP-2）的募集以及TCR介导的细胞信号转导的减弱。为确定淋巴细胞中PECAM-1抑制性信号传导的分子基础，该研究试图：（1）确定PECAM-1的ITIMs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；（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DT40 B细胞上表达的B细胞抗原受体的共连接导致钙动员显著减少——这与先前在T细胞中的观察结果相似。相比之下，缺乏ITIM的PECAM-1形式的共连接没有抑制作用。此外，尽管这些细胞中SHP-1水平丰富，但野生型PECAM-1无法减弱SHP-2缺陷型DT40变体中的钙动员。最后，PECAM-1在p56(lck)缺陷的Jurkat T细胞中未能发生酪氨酸磷酸化。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见解。
