P52Shc is required for CXCR4-dependent signaling and chemotaxis in T cells
P52Shc is required for CXCR4-dependent signaling and chemotaxis in T cells
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DOI：
10.1182/blood-2007-01-068411
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发表时间：
2007-09-15
期刊：
影响因子：
20.3
通讯作者：
Baldari, Cosima T.
中科院分区：
文献类型：
--
作者：
Patrussi, Laura;Ulivieri, Cristina;Baldari, Cosima T.
ShcA 是表面受体触发的 PTK 调节途径中 Ras/MAPK 激活的重要介质。该功能由组成型表达的 p52-kDa 同工型维持。除了激活 Ras 之外，p52Shc 还将 TCR 与 Rho GTPases 偶联，从而参与 T 细胞中肌动蛋白细胞骨架的重塑。在这里，我们讨论了 p52Shc 在 T 细胞趋化性中的潜在参与以及可磷酸化酪氨酸残基 YY239/240 和 Y317 在此过程中的作用。我们表明，CXCR4 与稳态趋化因子 SDF-1 α 的结合导致 p52Shc 磷酸化，并将其组装成包含 Lck、ZAP-70 和 Vav 的复合物。发现该过程与 Lck 和 Gi 相关。缺乏 YY239/240 或 Y317 的 p52Shc 突变体的表达，或 p52Shc 缺陷，导致 CXCR4 信号传导和 SDF-1 α 依赖性趋化性严重受损。强调 p52Shc 作为 CXCR4 信号级联的早期组成部分的关键作用。还发现 p52Shc 是配体依赖性 CXCR4 内化所必需的，与酪氨酸磷酸化无关。值得注意的是，CXCR4 的参与促进了 TCR/CD3 复合物 zeta 链的磷酸化，这对于 CXCR4 信号传导以及 SDF-1 α 依赖性受体内吞作用和趋化作用至关重要，表明 CXCR4 通过反式激活 TCR 发出信号。
ShcA is an important mediator of Ras/MAPK activation in PTK-regulated pathways triggered by surface receptors. This function is subserved by the constitutively expressed p52-kDa isoform. Besides activating Ras, p52Shc couples the TCR to Rho GTPases, and thereby participates in actin cytoskeleton remodeling in T cells. Here we have addressed the potential involvement of p52Shc in T-cell chemotaxis and the role of the phosphorylatable tyrosine residues, YY239/240 and Y317, in this process. We show that CXCR4 engagement by the homeostatic: chemokine, SDF-1 alpha, results in p52Shc phosphorylation and its assembly into a complex that includes Lck, ZAP-70, and Vav. This process was found to be both Lck and Gi dependent. Expression of p52Shc mutants lacking YY239/240 or Y317, or p52Shc deficiency, resulted in a profound impairment in CXCR4 signaling and SDF-1 alpha-dependent chemotaxis, urn. derscoring a crucial role of p52Shc as an early component of the CXCR4 signaling cascade. p52Shc was also found to be required for ligand-dependent CXCR4 internalization independently of tyrosine phosphorylation. Remarkably, CXCR4 engagement promoted phosphorylation of the zeta chain of the TCR/CD3 complex, which was found to be essential for CXCR4 signaling, as well as for SDF-1 alpha-dependent receptor endocytosis and chemotaxis, indicating that CXCR4 signals by transactivating the TCR.