Role Of Gα₁₃ In Cell Migration And Organ Regeneration

Gα13, a member of the heterotrimeric G proteins, is critical for actin cytoskeletal reorganization and cell migration. Previously we have shown that Gα13is 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 Gα13. Here, we show that PDGF can induce the phosphorylation of Ric-8A. Atypical protein kinase Cλ (aPKCλ) is required for Ric-8A phosphorylation. Furthermore, aPKCλ 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 Gα13and SOS1. SOS1functions as a guanine nucleotide exchange factor for Ras. Both Gα13and SOS1are important regulators of actin cytoskeleton reorganization and cell migration. Using endothelial cell-specific inducible Gα13knockout adult mice, we have shown that Gα13is critical for liver regeneration. The cellular mechanism is that Gα13is required for endothelial cell proliferation during the second-phase of liver regeneration. In the absence of Gα13, activation of the ERK MAPK pathway in endothelial cells is impaired, and the number of endothelial cells in liver is decreased. Gα13controls the Ras-ERK pathway by directly interacting with Sosl. Gα13binds to the Dbl-homology (DH) domain and increases the exchange activity of Sosl. Hence we have revealed a role for Gα13in organ regeneration and the underlying biochemical mechanism for Gα13regulating endothelial cell proliferation.