p140Cap dual regulation of E-cadherin/EGFR cross-talk and Ras signalling in tumour cell scatter and proliferation

被引:45
作者
Damiano, L. [1 ,2 ]
Di Stefano, P. [1 ,2 ]
Leal, M. P. Camacho [1 ,2 ]
Barba, M. [3 ]
Mainiero, F. [3 ]
Cabodi, S. [1 ,2 ]
Tordella, L. [1 ,2 ]
Sapino, A. [4 ]
Castellano, I. [4 ]
Canel, M.
Frame, M. [5 ]
Turco, E. [1 ,2 ]
Defilippi, P. [1 ,2 ]
机构
[1] Univ Turin, Dept Genet Biol & Biochem, I-10125 Turin, TO, Italy
[2] Univ Turin, Ctr Mol Biotechnol, I-10125 Turin, TO, Italy
[3] Univ Roma La Sapienza, Dept Expt Med & Pathol, Rome, Italy
[4] Univ Turin, Dept Biomed Sci & Human Oncol, I-10125 Turin, TO, Italy
[5] Western Gen Hosp, Edinburgh Canc Res Ctr, Edinburgh EH4 2XU, Midlothian, Scotland
关键词
cell motility; p140Cap; Ras; Src; tumour growth; BREAST-CANCER; EGF RECEPTOR; GROWTH; TUMORIGENESIS; PROGRESSION; ACTIVATION;
D O I
10.1038/onc.2010.128
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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
引用
收藏
页码:3677 / 3690
页数:14
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