p140Cap dual regulation of E-cadherin/EGFR cross-talk and Ras signalling in tumour cell scatter and proliferation
p140Cap dual regulation of E-cadherin/EGFR cross-talk and Ras signalling in tumour cell scatter and proliferation
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DOI：
10.1038/onc.2010.128
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发表时间：
2010-06-24
期刊：
影响因子：
8
通讯作者：
Defilippi, P.
中科院分区：
文献类型：
--
作者：
Damiano, L.;Di Stefano, P.;Defilippi, P.
衔接蛋白p140 Cap/SNIP是一种新的Src结合蛋白，通过C末端Src激酶（Csk）调控Src的活化。在这里，通过在乳腺癌和结肠癌细胞中获得和丧失功能的方法，我们报告了p140 Cap在细胞膜上固定E-钙粘蛋白，并抑制EGFR和Erk 1/2信号传导，阻断癌细胞的扩散和增殖。p140 Cap依赖性调节E-cadherin/EGFR的相互作用和细胞运动是由于Src激酶的抑制。然而，拯救Src活性不足以恢复Erk 1/2磷酸化和增殖。事实上，p140 Cap还通过影响EGFR下游的Ras活性来损害Erk 1/2磷酸化。总之，p140 Cap通过Src和Ras活性的双重控制稳定粘附连接并抑制EGFR和Ras信号传导，从而影响关键的癌症特性，如侵袭和生长。有趣的是，p140 Cap表达在更具侵袭性的人类乳腺癌中丢失，显示与EGFR表达呈负相关。因此，p140 Cap在机制上表现为抑制导致侵袭性表型的信号传导途径的肿瘤抑制剂。Oncogene（2010）29，3677-3690; doi：10.1038/onc.2010.128; 2010年5月10日在线发表
The adaptor protein p140Cap/SNIP is a novel Src-binding protein that regulates Src activation through C-terminal Src kinase (Csk). Here, by gain and loss of function approaches in breast and colon cancer cells, we report that p140Cap immobilizes E-cadherin at the cell membrane and inhibits EGFR and Erk1/2 signalling, blocking scatter and proliferation of cancer cells. p140Cap-dependent regulation of E-cadherin/EGFR cross-talk and cell motility is due to the inhibition of Src kinase. However, rescue of Src activity is not sufficient to restore Erk1/2 phosphorylation and proliferation. Indeed, p140Cap also impairs Erk1/2 phosphorylation by affecting Ras activity, downstream to the EGFR. In conclusion, p140Cap stabilizes adherens junctions and inhibits EGFR and Ras signalling through the dual control of both Src and Ras activities, thus affecting crucial cancer properties such as invasion and growth. Interestingly, p140Cap expression is lost in more aggressive human breast cancers, showing an inverse correlation with EGFR expression. Therefore, p140Cap mechanistically behaves as a tumour suppressor that inhibits signalling pathways leading to aggressive phenotypes.Oncogene (2010) 29, 3677-3690; doi: 10.1038/onc.2010.128; published online 10 May 2010