The role of tyrosine phosphorylation of cortactin in the locomotion of endothelial cells
The role of tyrosine phosphorylation of cortactin in the locomotion of endothelial cells
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DOI：
10.1074/jbc.273.40.25770
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发表时间：
1998-10-02
影响因子：
4.8
通讯作者：
Zhan, X
中科院分区：
文献类型：
--
作者：
Huang, C;Liu, JL;Zhan, X
Cortactin是一种丝状肌动蛋白交联蛋白，也是Src蛋白酪氨酸激酶的底物，在细胞外信号的刺激下，它在酪氨酸残基上被磷酸化。我们以前已经证明了Cortactin的丝状肌动蛋白的交联活性被Src(Huang，C.，Ni，Y.，Gao，Y.，HaudensChild，C.C.，和Jan，X.(1997)J.Biol Chem)减弱。272、13911-13915)。在体外，皮质蛋白的酪氨酸磷酸化特异地发生在富含脯氨酸序列和Src同源3结构域之间的区域。在该区域的9个酪氨酸残基中，Tyr(421)、Tyr(466)和Tyr(482)的突变在体外和体内都显著降低了Src介导的酪氨酸磷酸化。野生型Cortactin在ECV304中的异位表达导致细胞迁移增强。ECV304是一种自发转化的人脐静脉内皮细胞系。相反，酪氨酸磷酸化缺陷的皮质蛋白突变体的过度表达会损害内皮细胞的迁移。这些发现揭示了一种细胞内信号机制，通过这种机制，内皮细胞的运动性受到Src介导的皮质肌动蛋白酪氨酸磷酸化的调节。
Cortactin, a filamentous actin cross-linking protein and a substrate of Src protein tyrosine kinase, is phosphorylated at tyrosine residues upon stimulation by extracellular signals. We have previously demonstrated that the filamentous actin cross-linking activity of cortactin is attenuated by Src (Huang, C., Ni, Y., Gao, Y., Haudenschild, C. C,, and Zhan, X. (1997) J. Biol Chem. 272, 13911-13915). In vitro, tyrosine phosphorylation of cortactin occurs specifically within the region between the proline-rich sequence and the Src homology 3 domain. Among the nine tyrosine residues in this region, mutations at Tyr(421), Tyr(466), and Tyr(482) significantly reduced Src-meditated tyrosine phosphorylation both in vitro and in vivo. Ectopic expression of wild-type cortactin in ECV304, a spontaneously transformed human umbilical endothelial cell line, resulted in an enhanced cell migration. In contrast, overexpression of a cortactin mutant deficient in tyrosine phosphorylation impaired the migration of endothelial cells. These findings reveal an intracellular signaling mechanism whereby the motility of endothelial cells is regulated by a Src-mediated tyrosine phosphorylation of cortactin.