Talin1 phosphorylation activates β1 integrins: a novel mechanism to promote prostate cancer bone metastasis.
Talin1 phosphorylation activates β1 integrins: a novel mechanism to promote prostate cancer bone metastasis.
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Talins是一种接头蛋白，通过将整合素与细胞骨架结合来调节焦点黏附信号。Talins直接与整合素结合，是整合素激活所必需的。我们以前发现β-1整合素在转移性前列腺癌(Pca)细胞中被激活，增加了Pca向淋巴结和骨的转移。然而，β1整合素是如何在PCa细胞中被激活的尚不清楚。在本研究中，我们发现了一种新的β-1整合素激活机制。利用基因敲除实验，我们首先证明了talin1，而不是talin2，在β1整合素的激活中是重要的。接下来，我们发现talin1S425的磷酸化，而不是talin1的总表达，与PCa细胞的转移潜能相关。在talin1沉默的PC3-MM2和C4-2B4PCa细胞中表达非磷酸化突变体talin1S425A，降低了β1整合素的激活，整合素介导的黏附和运动，并增加了细胞对失巢凋亡的敏感性。相反，模拟磷酸化的突变体talin1S425D的重新表达导致β1整合素活性增加，并产生与talin1S425A表达相反的生物学效应。在高转移的PC3-MM2细胞中，不可磷酸化的突变体talin1S425A在talin1沉默的PC3-MM2细胞中的表达使其在心内注射后在骨中的定植能力丧失，而模拟磷酸化的突变体talin1S425D的重新表达恢复了其向骨转移的能力。免疫组织化学染色显示，与正常组织、原发肿瘤或淋巴结转移相比，人骨转移组织中talin S425的磷酸化水平显著增加。我们进一步表明，在转移的肿瘤细胞中，CDK5的激活剂p35的表达和CDK5的活性增加，并且CDK5的活性负责Talin1的磷酸化和随后的β1整合素的激活。总之，我们的研究揭示了CDK5介导的talin1的磷酸化导致β1整合素的激活是一种增加PCa细胞转移潜能的新机制。
Talins are adaptor proteins that regulate focal adhesion signaling by conjugating integrins to the cytoskeleton. Talins directly bind integrins and are essential for integrin activation. We previously showed that β1 integrins are activated in metastatic prostate cancer (PCa) cells, increasing PCa metastasis to lymph nodes and bone. However, how β1 integrins are activated in PCa cells is unknown. In this study, we identified a novel mechanism of β1 integrin activation. Using knockdown experiments, we first demonstrated talin1, but not talin2, is important in β1 integrin activation. We next showed that talin1 S425 phosphorylation, but not total talin1 expression, correlates with metastatic potential of PCa cells. Expressing a non-phosphorylatable mutant, talin1S425A, in talin1-silenced PC3-MM2 and C4-2B4 PCa cells, decreased activation of β1 integrins, integrin-mediated adhesion, motility, and increased the sensitivity of the cells to anoikis. In contrast, re-expression of the phosphorylation-mimicking mutant talin1S425D led to increased β1 integrin activation and generated biologic effects opposite to talin1S425A expression. In the highly metastatic PC3-MM2 cells, expression of a non-phosphorylatable mutant, talin1S425A, in talin1-silenced PC3-MM2 cells, abolished their ability to colonize in the bone following intracardiac injection, while re-expression of phosphorylation-mimicking mutant talin1S425D restored their ability to metastasize to bone. Immunohistochemical staining demonstrated that talin S425 phosphorylation is significantly increased in human bone metastases when compared to normal tissues, primary tumors, or lymph node metastases. We further showed that p35 expression, an activator of Cdk5, and Cdk5 activity were increased in metastatic tumor cells, and that Cdk5 kinase activity is responsible for talin1 phosphorylation and subsequent β1 integrin activation. Together, our study reveals Cdk5-mediated phosphorylation of talin1 leading to β1 integrin activation is a novel mechanism that increases metastatic potential of PCa cells.
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DOI：
10.1111/j.1742-4658.2009.06893.x
发表时间：
2009-03
期刊：
The FEBS journal
影响因子：
--
作者：
Debrand E;El Jai Y;Spence L;Bate N;Praekelt U;Pritchard CA;Monkley SJ;Critchley DR
通讯作者：
Critchley DR
DOI：
10.1016/b978-0-12-386039-2.00004-3
发表时间：
2011
影响因子：
--
作者：
Desiniotis A;Kyprianou N
通讯作者：
Kyprianou N
影响因子：
44.1
作者：
Song, Xianqiang;Yang, Jun;Qin, Jun
通讯作者：
Qin, Jun
DOI：
10.1158/1541-7786.mcr-12-0551
发表时间：
2013-04
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Lee YC;Jin JK;Cheng CJ;Huang CF;Song JH;Huang M;Brown WS;Zhang S;Yu-Lee LY;Yeh ET;McIntyre BW;Logothetis CJ;Gallick GE;Lin SH
通讯作者：
Lin SH
DOI：
10.1016/j.bbamem.2013.07.017
发表时间：
2014-02
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Das M;Ithychanda S;Qin J;Plow EF
通讯作者：
Plow EF