PTPL1/FAP-1 negatively regulates TRIP6 function in lysophosphatidic acid-induced cell migration
PTPL1/FAP-1 negatively regulates TRIP6 function in lysophosphatidic acid-induced cell migration
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DOI：
10.1074/jbc.m701499200
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发表时间：
2007-08-17
影响因子：
4.8
通讯作者：
Lin, Fang-Tsyr
中科院分区：
文献类型：
--
作者：
Lai, Yun-Ju;Lin, Weei-Chin;Lin, Fang-Tsyr
LIM结构域含有甲状腺激素受体相互作用蛋白6 (TRIP6)，是一种局点粘附分子，已知通过与LPA(2)受体相互作用来调节溶血磷脂酸（LPA）诱导的细胞迁移。LPA刺激将TRIP6靶向黏附复合物，并促进trir -55上TRIP6的c-Src依赖性磷酸化，从而为Crk Src同源2结构域创造一个对接位点，从而促进LPA诱导的形态改变和细胞迁移。在这里，我们进一步证明了从c- src介导的磷酸化到PTPL1/ fas相关磷酸酶1依赖的去磷酸化的转换在lppa诱导的细胞迁移中是TRIP6功能的抑制性反馈控制机制。PTPL1在体外使TRIP6的磷酸酪氨酸55去磷酸化，并抑制lpa诱导的细胞中TRIP6的酪氨酸磷酸化。这种负调控需要这两个分子与PTPL1的磷酸酶活性之间的直接蛋白-蛋白相互作用。与c-Src相比，PTPL1可阻止粘连部位的TRIP6周转。因此，lppa诱导的TRIP6与Crk的关联以及TRIP6促进lppa诱导的形态学改变和细胞迁移的功能被PTPL1抑制。总之，这些结果揭示了PTPL1磷酸酶在lppa诱导的细胞迁移中调节TRIP6功能的一种新机制。
The LIM domain-containing TRIP6 (Thyroid Hormone Receptor-interacting Protein 6) is a focal adhesion molecule known to regulate lysophosphatidic acid (LPA)-induced cell migration through interaction with the LPA(2) receptor. LPA stimulation targets TRIP6 to the focal adhesion complexes and promotes c-Src-dependent phosphorylation of TRIP6 at Tyr-55, which creates a docking site for the Crk Src homology 2 domain, thereby promoting LPA-induced morphological changes and cell migration. Here we further demonstrate that a switch from c-Src-mediated phosphorylation to PTPL1/Fas-associated phosphatase-1-dependent dephosphorylation serves as an inhibitory feedback control mechanism of TRIP6 function in LPA-induced cell migration. PTPL1 dephosphorylates phosphotyrosine 55 of TRIP6 in vitro and inhibits LPA-induced tyrosine phosphorylation of TRIP6 in cells. This negative regulation requires a direct protein-protein interaction between these two molecules and the phosphatase activity of PTPL1. In contrast to c-Src, PTPL1 prevents TRIP6 turnover at the sites of adhesions. As a result, LPA-induced association of TRIP6 with Crk and the function of TRIP6 to promote LPA-induced morphological changes and cell migration are inhibited by PTPL1. Together, these results reveal a novel mechanism by which PTPL1 phosphatase plays a counteracting role in regulating TRIP6 function in LPA-induced cell migration.