title: PAK1 kinase promotes cell motility and invasiveness through CRK-II serine phosphorylation in non-small cell lung cancer cells.
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.
authors: Division of Hematology/Oncology, West Los Angeles VA, Los Angeles, California, United States of America.
authors: Matthew
authors: M
authors: Rettig
authors: Kenny
authors: K
authors: Trinidad
authors: G
authors: G
authors: Pezeshkpour
authors: Patrick
authors: P
authors: Frost
authors: Sherven
authors: S
authors: Sharma
authors: Farhad
authors: F
authors: Moatamed
authors: Fuyuhiko
authors: F
authors: Tamanoi
authors: Fariborz
authors: F
authors: Mortazavi
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D051177:Catenins / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D050737:Proto-Oncogene Proteins c-crk / Q000737:chemistry* / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000378:metabolism*; D000095002:Delta Catenin
chemical_list: D051177:Catenins; D050737:Proto-Oncogene Proteins c-crk; D012694:Serine; D054462:p21-Activated Kinases; D000095002:Delta Catenin; C000722347:CTNND1 protein, human