Differing contributions of LIMK and ROCK to TGFβ-induced transcription, motility and invasion

摘要: The ability of transforming growth factor β (TGFβ) to induce epithelial-mesenchymal transition (EMT) is mediated by SMAD-dependent and SMAD-independent pathways such as the activation Rho GTPase signalling. Upon activation, GTP-bound stimulates ROCK kinases, which in turn phosphorylate numerous substrates including LIM kinases (LIMK). net result increased actin-myosin contractile force generation, with a contribution from LIMK-induced actin filament stabilisation. In this study, we made use siRNA-mediated knockdown selective inhibitors determine contributions LIMK TGFβ-induced responses. We find that both are required for TGFβ stimulation serum-response (SRF) transcriptional activity stress fibre formation during EMT. contrast, although inhibition had little effect on cell motility scratch wound Transwell migration assays, actually promoted helping individual cells break free epithelial sheet. Furthermore, demonstrate LIMK, but not ROCK, effectively blocked driven invasion through layer matrigel extracellular matrix protein. These results indicate roles signalling pathway downstream identical suggest represents an attractive therapeutic target organ fibrosis metastatic cancer spread.