Max Planck Institute for Molecular Biomedicine, Department of Vascular Cell Biology, Münster, Germany.
Eur J Immunol. 2010 Nov;40(11):3220-5. doi: 10.1002/eji.201040313.
The hematopoietic progenitor kinase 1 (HPK1) signals into MAPK and NFκB pathways downstream of immunoreceptors, but enigmatically is a negative regulator of leukocytes. Here, we report a novel role for HPK1 in regulating the activation of the adhesion molecule leukocyte function-associated antigen-1 (LFA-1). Upon TCR stimulation, mediated by binding of adhesion and degranulation promoting adaptor protein (ADAP) to SLP-76, a ternary complex composed of ADAP/55-kDa src kinase associated phosphoprotein (SKAP-55) and RIAM translocates to the membrane and causes membrane recruitment of the active small GTPase Ras-related protein 1 (Rap1). Active Rap1, via its binding to RapL (regulator for cell adhesion and polarization enriched in lymphoid tissues), mediates LFA-1 integrin activation. We show here that HPK1, which also binds SLP-76, compete with ADAP for SLP-76 binding. In addition, HPK1 dampens Rap1 activation, resulting in decreased LFA-1 activity. Analysis of HPK1-deficient T cells revealed increased ADAP recruitment to SLP-76 and elevated Rap1 activation in those cells, leading to increased adhesion to ICAM-1 and cell spreading. Altogether, these results describe a novel function for HPK1 in linking TCR signaling to cell adhesion regulation and provide a mechanistic explanation for the negative regulatory role of HPK1 in T-cell biology.
造血祖细胞激酶 1（HPK1）在免疫受体下游的 MAPK 和 NFκB 途径中发出信号，但令人费解的是，它是白细胞的负调节剂。在这里，我们报告了 HPK1 在调节粘附分子白细胞功能相关抗原-1（LFA-1）的激活中的新作用。在 TCR 刺激下，通过结合粘附和脱颗粒促进衔接蛋白（ADAP）与 SLP-76，由 ADAP/55-kDa src 激酶相关磷酸蛋白（SKAP-55）和 RIAM 组成的三元复合物易位到膜上，并导致活性小分子 GTP 酶 Ras 相关蛋白 1（Rap1）的膜募集。活性 Rap1 通过与其结合 RapL（富含淋巴细胞组织的细胞粘附和极化调节剂），介导 LFA-1 整合素的激活。我们在这里表明，也与 SLP-76 结合的 HPK1 与 ADAP 竞争 SLP-76 的结合。此外，HPK1 抑制 Rap1 的激活，导致 LFA-1 活性降低。对 HPK1 缺陷 T 细胞的分析表明，ADAP 向 SLP-76 的募集增加，以及这些细胞中 Rap1 的激活增加，导致与 ICAM-1 的粘附增加和细胞铺展。总之，这些结果描述了 HPK1 在将 TCR 信号与细胞粘附调节联系起来的新功能，并为 HPK1 在 T 细胞生物学中的负调节作用提供了机制解释。
