Phosphorylation of the integrin α4 cytoplasmic domain regulates paxillin binding
Phosphorylation of the integrin α4 cytoplasmic domain regulates paxillin binding
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DOI：
10.1074/jbc.m102665200
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发表时间：
2001-11-02
影响因子：
4.8
通讯作者：
Ginsberg, MH
中科院分区：
文献类型：
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作者：
Han, JW;Liu, SC;Ginsberg, MH
α4 整合素对于胚胎发生、造血、炎症和免疫反应至关重要，这可能是因为 α(4) 整合素具有与其他整合素不同的信号传导特性。具体来说，α (4) 胞质结构域与桩蛋白（一种信号转接蛋白）紧密结合，导致细胞迁移增加和细胞骨架组织改变，从而导致细胞扩散减少。 α (4) 尾包含聚集在其核心桩蛋白结合区域的潜在磷酸化位点。我们现在报道 α (4) 尾在体外和体内均被磷酸化。此外，Ser(988) 是主要的磷酸化位点。使用针对 Ser(988)-磷酸化 α (4) 的特异性抗体，我们发现不同细胞中 a4 磷酸化的化学计量有所不同。然而，在 Jurkat T 细胞中，> 60% 的 a4 被磷酸化。 Ser(988) 处的磷酸化可阻断桩蛋白与 alpha (4) 尾部的结合。 α (4) 的磷酸化模拟突变体 (α (4)S988D) 阻断桩蛋白结合并逆转 α (4) 对细胞扩散的抑制作用。因此，α (4) 磷酸化是调节桩蛋白与 α (4) 整合素结合的生化机制，从而调节 α (4) 整合素依赖性细胞功能。
alpha4 integrins are essential for embryogenesis, hematopoiesis, inflammation, and immune response possibly because alpha (4) integrins have distinct signaling properties from other integrins. Specifically, the alpha (4) cytoplasmic domain binds tightly to paxillin, a signaling adaptor protein, leading to increased cell migration and an altered cytoskeletal organization that results in reduced cell spreading. The alpha (4) tail contains potential phosphorylation sites clustered in its core paxillin binding region. We now report that the alpha (4) tail is phosphorylated in vitro and in viva. Furthermore, Ser(988) is a major phosphorylation site. Using antibodies specific for Ser(988)- phosphorylated alpha (4), we found the stoichiometry of a4 phosphorylation varied in different cells. However, > 60% of a4 was phosphorylated in Jurkat T cells. Phosphorylation at Ser(988) blocked paxillin binding to the alpha (4) tail. A phosphorylation-mimicking mutant of alpha (4) (alpha (4)S988D) blocked paxillin binding and reversed the inhibitory effect of alpha (4) on cell spreading. Consequently, alpha (4) phosphorylation is a biochemical mechanism to modulate paxillin binding to alpha (4) integrins with consequent regulation of alpha (4) integrin-dependent cellular functions.