Abstract
The role of c-Crk (CRK) in promoting metastasis is well described however the role of CRK phosphorylation and the corresponding signaling events are not well explained. We have observed CRK-II serine 41 phosphorylation is inversely correlated with p120-catenin and E-cadherin expressions in non-small cell lung cancer (NSCLC) cells. Therefore, we investigated the role of CRK-II serine 41 phosphorylation in the down-regulation of p120-catenin, cell motility and cell invasiveness in NSCLC cells. For this purpose, we expressed phosphomimetic and phosphodeficient CRK-II serine 41 mutants in NSCLC cells. NSCLC cells expressing phosphomimetic CRK-II seine 41 mutant showed lower p120-catenin level while CRK-II seine 41 phosphodeficient mutant expression resulted in higher p120-catenin. In addition, A549 cells expressing CRK-II serine 41 phosphomimetic mutant demonstrated more aggressive behavior in wound healing and invasion assays and, on the contrary, expression of phosphodeficient CRK-II serine 41 mutant in A549 cells resulted in reduced cell motility and invasiveness. We also provide evidence that PAK1 mediates CRK-II serine 41 phosphorylation. RNAi mediated silencing of PAK1 increased p120-catenin level in A549 and H157 cells. Furthermore, PAK1 silencing decreased cell motility and invasiveness in A549 cells. These effects were abrogated in A549 cells expressing phosphomimetic CRK-II serine 41. In summary, these data provide evidence for the role of PAK1 in the promotion of cell motility, cell invasiveness and the down regulation of p120-catenin through CRK serine 41 phosphorylation in NSCLC cells.
Highlights
Development of metastatic lesions in most solid tumors result in an incurable condition by today’s treatment modalities
CRK does not contain a catalytic domain both tyrosine and serine kinase activities have been associated with CRK [15]
We recently reported that CRK mediates transcriptional repression of p120-catenin (CTNND1) in non-small cell lung cancer (NSCLC) cells
Summary
Development of metastatic lesions in most solid tumors result in an incurable condition by today’s treatment modalities. As a member of adherens junction, p120-catenin (p120ctn) plays an important role in cell-cell adhesions and loss of p120-catenin expression results in destabilization of the cadherin-catenin complex thereby promoting tumor invasion and metastasis [1,2,3,4,5,6,7,8,9,10]. Considering downregulation of p120-catenin in non-small cell lung cancer (NSCLC) is transcriptionally mediated [11], an investigation in the upstream signaling events that could result in transcriptional repression of p120-catenin (CTNND1), lead us to adaptor protein CRK and its role in the repression of p120-catenin [12]. The central position of CRK in signaling cascades makes it likely that CRK affects several downstream targets, other than the p120-catenin (CTNND1) promoter, thereby promoting tumor progression, invasion and metastasis
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