Department of Biochemistry, School of Medicine, West Virginia University, Morgantown, West Virginia, WV 26506, USA.
Mol Cancer Res. 2013 Jun;11(6):651-64. doi: 10.1158/1541-7786.MCR-12-0578. Epub 2013 Mar 19.
The Src homology phosphotyrosyl phosphatase 2 (SHP2) is a positive effector of receptor tyrosine kinases (RTK) 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 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 nonstimulated cells seems FAK independent as 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.
Src 同源磷酸酪氨酸磷酸酶 2（SHP2）是受体酪氨酸激酶（RTK）信号的正向效应物。此外，已知 SHP2 可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，SHP2 调节细胞运动的机制尚未完全阐明。在本报告中，提出了 SHP2 调节细胞迁移的新作用。我们表明，SHP2 通过介导片状伪足的持久性和细胞极性来调节 MDA-MB231 和 MDA-MB468 基底样和三阴性乳腺癌细胞系的定向细胞迁移。我们进一步表明，SHP2 通过去磷酸化 pTyr397 来调节粘着斑激酶（FAK）的活性，pTyr397 是激活 FAK 功能的自身磷酸化位点。由于已知 FAK 的过度激活会阻止新生粘着斑复合物向粘着斑的成熟，因此我们提出，SHP2 促进片状伪足持久性的机制之一是通过去磷酸化 pTyr397 来下调 FAK 活性。FAK 活性的抑制部分恢复了 SHP2 沉默细胞中 EGF 诱导的片状伪足持久性和细胞迁移的发现支持了我们的观点，即 SHP2 通过作用于 FAK（至少部分）来促进生长因子诱导的细胞运动。然而，SHP2 抑制在非刺激细胞中的作用似乎与 FAK 无关，因为在对照和 SHP2 沉默细胞中 pY397-FAK 水平没有显着差异。此外，FAK 抑制不能挽救 SHP2 沉默细胞中的高尔基取向缺陷，这表明 SHP2 通过其他机制发挥作用以促进细胞极性。
