Phosphorylated Caveolin-1 Regulates Rho/ROCK-Dependent Focal Adhesion Dynamics and Tumor Cell Migration and Invasion
Phosphorylated Caveolin-1 Regulates Rho/ROCK-Dependent Focal Adhesion Dynamics and Tumor Cell Migration and Invasion
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DOI：
10.1158/0008-5472.can-08-0343
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发表时间：
2008-10-15
期刊：
影响因子：
11.2
通讯作者：
Nabi, Ivan R.
中科院分区：
文献类型：
--
作者：
Joshi, Bharat;Strugnell, Scott S.;Nabi, Ivan R.
Rho/ROCK信号和小窝蛋白-1(Cav1)参与了肿瘤细胞的迁移和转移，但其潜在的分子机制尚不清楚。Cav1被发现是乳腺癌和直肠癌患者生存率下降的独立预测因子，并与结肠癌患者存在远处转移显著相关。Rho/ROCK信号通过Cav1酪氨酸(Y14)磷酸化调节焦点黏附(FA)动态，从而促进肿瘤细胞迁移。Cav1的磷酸化定位于肿瘤细胞的突起区域，而Cav1的酪氨酸磷酸化依赖于Src激酶和Rho/ROCK信号。在不同组织来源的转移性肿瘤细胞中，磷酸化Cav1水平的升高与GTP-RhoA水平的升高有关。Cav1在肿瘤细胞中的稳定表达和敲除研究表明，Cav1的磷酸化表达刺激Rho激活，稳定FAK与FAs的关联，并以岩石依赖和Src依赖的方式促进细胞迁移和侵袭。因此，酪氨酸磷酸化的Cav1作为Rho/ROCK信号的效应器，调节FA的周转，从而调节肿瘤细胞的迁移和侵袭。这些研究确定了肿瘤细胞突起中Rho/ROCK、Src和磷酸化Cav1之间的反馈环，确定了Cav1在肿瘤转移中的一个新功能，这可能是导致一些表达Cav1的肿瘤预后不良的原因之一。[癌症资源2008；68(20)：8210-20]
Rho/ROCK signaling and caveolin-1 (Cav1) are implicated in tumor cell migration and metastasis; however, the underlying molecular mechanisms remain poorly defined. Cav1 was found here to be an independent predictor of decreased survival in breast and rectal cancer and significantly associated with the presence of distant metastasis for colon cancer patients. Rho/ROCK signaling promotes tumor cell migration by regulating focal adhesion (FA) dynamics through tyrosine (Y14) phosphorylation of Cav1. Phosphorylated Cav1 is localized to protrusive domains of tumor cells and Cav1 tyrosine phosphorylation is dependent on Src kinase and Rho/ROCK signaling. Increased levels of phosphorylated Cav1 were associated with elevated GTP-RhoA levels in metastatic tumor cells of various tissue origins. Stable expression and knockdown studies of Cav1 in tumor cells showed that phosphorylated Cav1 expression stimulates Rho activation, stabilizes FAK association with FAs, and promotes cell migration and invasion in a ROCK-dependent and Src-dependent manner. Tyrosine-phosphorylated Cav1, therefore, functions as an effector of Rho/ROCK signaling in the regulation of FA turnover and, thereby, tumor cell migration and invasion. These studies define a feedback loop between Rho/ROCK, Src, and phosphorylated Cav1 in tumor cell protrusions, identifying a novel function for Cav1 in tumor metastasis that may contribute to the poor prognosis of some Cav1-expressing tumors. [Cancer Res 2008;68(20):8210-20]