Role Of G?₁₃ In Cell Migration And Organ Regeneration

G?13, a member of the heterotrimeric G proteins, is critical for actin cytoskeletal reorganization and cell migration. Previously we have shown that G?13is essential for both G protein-coupled Receptor (GPCR) and receptor tyrosine kinase (RTK)-induced actin cytoskeletal reorganization such as dynamic dorsal ruffle turnover and cell migration. Ric-8A, a non-receptor guanine nucleotide exchange factor for some heterotrimeric G proteins, is critical for coupling receptor tyrosine kinases to G?13. Here, we show that PDGF can induce the phosphorylation of Ric-8A. Atypical protein kinase C? (aPKC?) is required for Ric-8A phosphorylation. Furthermore, aPKC? is required for PDGF-induced dorsal ruffle turnover and cell migration as demonstrated by both down-regulation of aPKCX protein levels in cells by RNA interference and by studies in aPKCX knock-out cells. Moreover, phosphorylation of Ric-8A modulates its subcellular localization. Hence, aPKCX is critical for PDGF-induced actin cytoskeletal reorganization and cell migrationWe also studied the interaction of G?13and SOS1. SOS1functions as a guanine nucleotide exchange factor for Ras. Both G?13and SOS1are important regulators of actin cytoskeleton reorganization and cell migration. Using endothelial cell-specific inducible G?13knockout adult mice, we have shown that G?13is critical for liver regeneration. The cellular mechanism is that G?13is required for endothelial cell proliferation during the second-phase of liver regeneration. In the absence of G?13, activation of the ERK MAPK pathway in endothelial cells is impaired, and the number of endothelial cells in liver is decreased. G?13controls the Ras-ERK pathway by directly interacting with Sosl. G?13binds to the Dbl-homology (DH) domain and increases the exchange activity of Sosl. Hence we have revealed a role for G?13in organ regeneration and the underlying biochemical mechanism for G?13regulating endothelial cell proliferation.