Nolz Jeffrey C, Nacusi Lucas P, Segovis Colin M, Medeiros Ricardo B, Mitchell Jason S, Shimizu Yoji, Billadeau Daniel D
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
J Cell Biol. 2008 Sep 22;182(6):1231-44. doi: 10.1083/jcb.200801121.
WAVE2 regulates T cell receptor (TCR)-stimulated actin cytoskeletal dynamics leading to both integrin clustering and affinity maturation. Although WAVE2 mediates integrin affinity maturation by recruiting vinculin and talin to the immunological synapse in an Arp2/3-dependent manner, the mechanism by which it regulates integrin clustering is unclear. We show that the Abl tyrosine kinase associates with the WAVE2 complex and TCR ligation induces WAVE2-dependent membrane recruitment of Abl. Furthermore, we show that WAVE2 regulates TCR-mediated activation of the integrin regulatory guanosine triphosphatase Rap1 via the recruitment and activation of the CrkL-C3G exchange complex. Moreover, we demonstrate that although Abl does not regulate the recruitment of CrkL-C3G into the membrane, it does affect the tyrosine phosphorylation of C3G, which is required for its guanine nucleotide exchange factor activity toward Rap1. This signaling node regulates not only TCR-stimulated integrin clustering but also affinity maturation. These findings identify a previously unknown mechanism by which the WAVE2 complex regulates TCR signaling to Rap1 and integrin activation.
WAVE2调节T细胞受体（TCR）刺激的肌动蛋白细胞骨架动力学，导致整合素聚集和亲和力成熟。虽然WAVE2通过以Arp2/3依赖的方式将纽蛋白和桩蛋白募集到免疫突触来介导整合素亲和力成熟，但其调节整合素聚集的机制尚不清楚。我们发现Abl酪氨酸激酶与WAVE2复合物相关联，TCR连接诱导Abl以WAVE2依赖的方式募集到膜上。此外，我们表明WAVE2通过募集和激活CrkL-C3G交换复合物来调节TCR介导的整合素调节鸟苷三磷酸酶Rap1的激活。此外，我们证明虽然Abl不调节CrkL-C3G募集到膜上，但它确实影响C3G的酪氨酸磷酸化，这是其对Rap1的鸟嘌呤核苷酸交换因子活性所必需的。这个信号节点不仅调节TCR刺激的整合素聚集，还调节亲和力成熟。这些发现确定了一种以前未知的机制，通过该机制WAVE2复合物调节TCR向Rap1的信号传导和整合素激活。
