The tyrosine phosphatase SHP2 regulates focal adhesion kinase to promote EGF-induced lamellipodia persistence and cell migration.
The tyrosine phosphatase SHP2 regulates focal adhesion kinase to promote EGF-induced lamellipodia persistence and cell migration.
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DOI：
10.1158/1541-7786.mcr-12-0578
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发表时间：
2013-06
期刊：
影响因子：
--
通讯作者：
Agazie YM
中科院分区：
文献类型：
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作者：
Hartman ZR;Schaller MD;Agazie YM
Src同源性磷酸酪氨酸磷酸酶2（SHP 2）是受体酪氨酸激酶（RTK）信号传导的正效应子。此外，已知SHP 2促进细胞迁移和侵袭，这是癌症转移的关键步骤。然而，迄今为止，SHP 2调节细胞运动的机制尚未完全了解。在本报告中，SHP 2在调节细胞迁移中的新作用已经被提出。我们发现，SHP 2介导板状伪足持久性和细胞极性，以促进MDA-MB 231和MDA-MB 468基底样和三阴性乳腺癌细胞系中的定向细胞迁移。我们进一步表明，SHP 2调节粘着斑激酶（FAK）的活性，通过去磷酸化pTyr 397，启动FAK功能的自磷酸化位点。由于已知FAK的过度活化对抗新生局灶性复合物向局灶性粘连的成熟，我们提出SHP 2促进板状伪足持久性的机制之一是通过pTyr 397的去磷酸化下调FAK活性。FAK活性的抑制部分恢复表皮生长因子（EGF）诱导的片状伪足的持久性和细胞迁移SHP 2沉默细胞的发现支持我们的主张，SHP 2促进生长因子诱导的细胞运动的作用，至少部分，FAK。然而，在未刺激的细胞中SHP 2抑制的作用似乎不依赖于FAK，因为在对照和SHP 2沉默的细胞之间在pY 397-FAK水平上没有显著差异。此外，FAK抑制没有拯救高尔基体的方向缺陷，在SHP 2沉默的细胞，表明SHP 2通过其他机制，以促进细胞极性。
The Src homology phosphotyrosyl phosphatase2 (SHP2) is a positive effector of receptor tyrosine kinases (RTKs) signaling. Furthermore, SHP2 is known to promote cell migration and invasiveness, key steps in cancer metastasis. To date, however, the mechanism by which SHP2 regulates cell movement is not fully understood. In the current report, a new role for SHP2 in regulating cell migration has been suggested. We show that SHP2 mediates lamellipodia persistence and cell polarity to promote directional cell migration in the MDA-MB231 and the MDA-MB468 basal-like and triple-negative breast cancer cell lines. We further show that SHP2 modulates the activity of focal adhesion kinase (FAK) by dephosphorylating pTyr397, the autophosphorylation site that primes FAK function. Because hyperactivation of FAK is known to counter the maturation of nascent focal complexes to focal adhesions, we propose that one of the mechanisms by which SHP2 promotes lamellipodia persistence is by downregulating FAK activity through dephosphorylation of pTyr397. The finding that inhibition of FAK activity partially restores epidermal growth factor (EGF)-induced lamellipodia persistence and cell migration in SHP2-silenced cells supports our proposition that SHP2 promotes growth-factor-induced cell movement by acting, at least in part, on FAK. However, the effect of SHP2 inhibition in non-stimulated cells seems FAK independent since there was no significant difference between the control and the SHP2-silenced cells in pY397-FAK levels. Also, FAK inhibition did not rescue golgi orientation defects in SHP2-silenced cells, suggesting that SHP2 acts through other mechanisms to promote cell polarity.