c-Src-mediated phosphorylation of TRIP6 regulates its function in lysophosphatidic acid-induced cell migration
c-Src-mediated phosphorylation of TRIP6 regulates its function in lysophosphatidic acid-induced cell migration
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DOI：
10.1128/mcb.25.14.5859-5868.2005
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发表时间：
2005-07-01
影响因子：
5.3
通讯作者：
Lin, FT
中科院分区：
文献类型：
--
作者：
Lai, YJ;Chen, CS;Lin, FT
TRIP 6（甲状腺受体相互作用蛋白6），也称为ZRP-1（zyxin-related protein 1），是zyxin家族的成员，与细胞运动有关。以前我们已经证明TRIP 6与LPA（2）受体结合，并以激动剂依赖性方式与焦点复合物的几种组分结合，从而增强溶血磷脂酸（LPA）诱导的细胞迁移。在这里，我们进一步报告，TRIP 6在LPA信号转导的功能是由c-Src介导的TRIP 6的酪氨酸-55残基的磷酸化。LPA刺激诱导NIH 3 T3细胞和表达c-Src的成纤维细胞中内源性TRIP 6的酪氨酸磷酸化，其在Src缺失的成纤维细胞中几乎被消除。引人注目的是，TRIP 6的磷酸酪氨酸-55和脯氨酸-58残基都是体外和细胞中Crk结合所需的。Tyr-55突变为Phe不会改变TRIP 6定位于粘着斑或与肌动蛋白结合的能力。然而，它消除了TRIP 6与细胞中Crk和p130（cas）的结合，并显著降低了TRIP 6促进LPA诱导的ERK活化的功能。最终，这些信号事件控制TRIP 6在促进LPA诱导的形态学变化和细胞迁移中的功能。
TRIP6 (thyroid receptor-interacting protein 6), also known as ZRP-1 (zyxin-related protein 1), is a member of the zyxin family that has been implicated in cell motility. Previously we have shown that TRIP6 binds to the LPA(2) receptor and associates with several components of focal complexes in an agonist-dependent manner and, thus, enhances lysophosphatidic acid (LPA)-induced cell migration. Here we further report that the function of TRIP6 in LPA signaling is regulated by c-Src-mediated phosphorylation of TRIP6 at the Tyr-55 residue. LPA stimulation induces tyrosine phosphorylation of endogenous TRIP6 in NIH 3T3 cells and c-Src-expressing fibroblasts, which is virtually eliminated in Src-null fibroblasts. Strikingly, both phosphotyrosine-55 and proline-58 residues of TRIP6 are required for Crk binding in vitro and in cells. Mutation of Tyr-55 to Phe does not alter the ability of TRIP6 to localize at focal adhesions or associate with actin. However, it abolishes the association of TRIP6 with Crk and p130(cas) in cells and significantly reduces the function of TRIP6 to promote LPA-induced ERK activation. Ultimately, these signaling events control TRIP6 function in promoting LPA-induced morphological changes and cell migration.