Abstract
Although cell migration plays a central role in development and disease, the underlying molecular mechanism is not fully understood. Here we report that a phosphorylation-mediated molecular switch comprising deleted in liver cancer 1 (DLC1), tensin-3 (TNS3), phosphatase and tensin homologue (PTEN) and phosphoinositide-3-kinase (PI3K) controls the spatiotemporal activation of the small GTPases, Rac1 and RhoA, thereby initiating directional cell migration induced by growth factors. On epidermal growth factor (EGF) or platelet-derived growth factor (PDGF) stimulation, TNS3 and PTEN are phosphorylated at specific Thr residues, which trigger the rearrangement of the TNS3–DLC1 and PTEN–PI3K complexes into the TNS3–PI3K and PTEN–DLC1 complexes. Subsequently, the TNS3–PI3K complex translocates to the leading edge of a migrating cell to promote Rac1 activation, whereas PTEN–DLC1 translocates to the posterior for localized RhoA activation. Our work identifies a core signalling mechanism by which an external motility stimulus is coupled to the spatiotemporal activation of Rac1 and RhoA to drive directional cell migration.
Highlights
Cell migration plays a central role in development and disease, the underlying molecular mechanism is not fully understood
We have shown recently that TNS3 markedly enhances the RhoGAP activity of deleted in liver cancer 1 (DLC1) by converting the latter from an auto-inhibited to an active state[18]
We find that epidermal growth factor (EGF) signalling leads to the phosphorylation of TNS3 and phosphatase and tensin homologue (PTEN), which, in turn, prompts a switch of binding partners for TNS3 and PTEN such that the TNS3–DLC1 and PTEN–PI3K complexes are dissolved to form the TNS3–PI3K and PTEN–DLC1 complexes
Summary
Cell migration plays a central role in development and disease, the underlying molecular mechanism is not fully understood. We report that a phosphorylationmediated molecular switch comprising deleted in liver cancer 1 (DLC1), tensin-3 (TNS3), phosphatase and tensin homologue (PTEN) and phosphoinositide-3-kinase (PI3K) controls the spatiotemporal activation of the small GTPases, Rac[1] and RhoA, thereby initiating directional cell migration induced by growth factors. The Rho family of small GTPases, to which RhoA, Rac[1] and Cdc[42] belong, plays an essential role in cell migration by promoting cytoskeletal reorganization necessary for motility[4,5,6]. It has been shown that PIP3 promotes Rac[1] activation by recruiting Tiam[1], a PH domain-containing GEF, to the leading edge of migrating cells[24,25]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have