C-Abl Kinase Regulates Cell Proliferation And Ionizing Radiation-Induced G2/M Arrest Via Phosphorylation Of Fhl2

Nonreceptor tyrosine kinase c-Abl participates in several cellular processes by phosphorylating transcription factors or cofactors. c-Abl binds and phosphorylates four-and-a-half-LIM-only protein 2 (FHL2), but the identity of the phosphorylation sites and their contribution to cell cycle regulation is unclear. In this study, we demonstrate that c-Abl highly phosphorylates FHL2 at Y97, Y176, Y217, and Y236 through mass spectrometry and tyrosine-to-phenylalanine (Y -> F) mutant analysis. Proliferation was inhibited in cells expressing wild-type (WT) FHL2 but not cells expressing the phosphorylation-defective mutant FHL2(4YF). Moreover, FHL2 contributed to cell cycle arrest at G2/M induced by ionizing radiation (IR). FHL2 WT but not FHL2(4YF) rescued FHL2 function in FHL2-depleted cells by causing IR-induced G2/M arrest. These results demonstrate that c-Abl regulates cell cycle progression by phosphorylating FHL2.