PAK1 kinase promotes cell motility and invasiveness through CRK-II serine phosphorylation in non-small cell lung cancer cells

PLoS One. 2012;7(7):e42012. doi: 10.1371/journal.pone.0042012. Epub 2012 Jul 27.

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.

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Catenins / genetics
  • Cell Line, Tumor
  • Cell Movement*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / pathology*
  • Neoplasm Invasiveness
  • Phosphorylation
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins c-crk / chemistry*
  • Proto-Oncogene Proteins c-crk / metabolism*
  • Serine / metabolism*
  • p21-Activated Kinases / metabolism*

Substances

  • Catenins
  • Proto-Oncogene Proteins c-crk
  • delta catenin
  • Serine
  • p21-Activated Kinases

Grant support

The authors have no support or funding to report.