REGULATION OF RHOGAP DLC1 BY FAK, PP2A AND MEK/ERK IN CELL DYNAMICS

Abstract

DLC1, a functional RhoGAP and tumor suppressor, affects the process of cell migration via its regulation of RhoA. A serine-rich multi-domain protein, DLC1 undergoes post-translational modifications such as phosphorylation. It has been identified as a downstream target for various kinases but effects of growth factors, which play a crucial role in the development and progression of cancer, on DLC1 have not yet been elucidated. We have identified a novel pathway involving the concerted action of Ras/Mek/Erk pathway, Focal adhesion kinase (FAK) and Protein phosphatase-2A (PP2A) to activate DLC1s GAP function. EGF stimulation not only leads to the phosphorylation of DLC1 but also that of FAK to inactivate it, thus allowing PP2A-mediated dephosphorylation at a secondary site on DLC1. This signalling cascade directly affects DLC1s effect on cell spreading and migration, which can be correlated to the reduced RhoA levels.