Role Of Gα₁₃ In Actin Cytoskeletal Reorganization And Cell Migration

Heterotrimeric G proteins are critical transducers of cellular signaling. In addition to their classic roles in relaying signals from G protein-coupled receptors (GPCRs), heterotrimeric G proteins also mediate physiological functions from non-GPCRs. Previously we have shown that Gα13, a member of the heterotrimeric G proteins, is essential for growth factor receptor-induced actin cytoskeletal reorganization such as dynamic dorsal ruffle turnover and cell migration. These Gα13-mediated dorsal ruffle turnover and cell migration by growth factors acting on their receptor tyrosine kinases (RTKs) are independent of GPCRs. However, the mechanism by which RTKs signal to Gα13is not known. Here we show that Ric-8A, a non-receptor guanine nucleotide exchange factor for some heterotrimeric G proteins, is critical for coupling RTKs to Gα13. Down-regulation of Ric-8A protein levels in cells by RNA interference slowed down platelet-derived growth factor (PDGF)-induced dorsal ruffle turnover and inhibited PDGF-initiated cell migration. PDGF was able to increase the activity of Ric-8A in cells. Furthermore, purified Ric-8A proteins directly interact with purified Gα13protein in a nucleotide-dependent manner. Deficiency of Ric-8A prevented the membrane translocation of Gα13. Hence, Ric-8A is critical for growth factor receptor-induced actin cytoskeletal reorganization.We also studied the interaction mechanism of Gα13and the tyrosine kinase Abl and the role of this interaction in cytoskeleton reorganization and cell migration. Inhibition of this interaction affected both dorsal ruffle turn over and cell migration. Both Gα13and Abl are important regulator of actin cytoskeleton and cell migration, but their function may be different, or even opposite. The novel interaction we described here may shed light on how do they coordinate each other and regulate cell migration together.