title: Resistance to inhibitors of cholinesterase-8A (Ric-8A) is critical for growth factor receptor-induced actin cytoskeletal reorganization.
abstract: 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 Gα(13), 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 Gα(13)-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 Gα(13) is not known. Here, we show that cholinesterase-8A (Ric-8A), a nonreceptor guanine nucleotide exchange factor for some heterotrimeric G proteins, is critical for coupling RTKs to Gα(13). 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 interact directly with purified Gα(13) protein in a nucleotide-dependent manner. Deficiency of Ric-8A prevented the translocation of Gα(13) to the cell cortex. Hence, Ric-8A is critical for growth factor receptor-induced actin cytoskeletal reorganization.
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China 430072.
authors.forename: Limin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Physiology, Cornell University Weill Medical College, New York, New York 10065.
authors.forename: Dagang
authors.initials: D
authors.lastname: Guo
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China 430072.
authors.forename: Bowen
authors.initials: B
authors.lastname: Xing
authors.affiliation: Department of Physiology, Cornell University Weill Medical College, New York, New York 10065.
authors.forename: J Jillian
authors.initials: JJ
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China 430072.
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Shu
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China 430072.
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China 430072. Electronic address: xyhuang@med.cornell.edu.
authors.forename: Xin-Yun
authors.initials: XY
authors.lastname: Huang
mesh_terms: D000199:Actins / Q000737:chemistry*; D000818:Animals; D002465:Cell Movement; D003599:Cytoskeleton / Q000378:metabolism*; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D017978:Receptors, Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D014945:Wound Healing
chemical_list: D000199:Actins; D020662:Guanine Nucleotide Exchange Factors; D017978:Receptors, Growth Factor; C561938:Ric8A protein, human; C485884:Ric8a protein, mouse; D005982:Glutathione Transferase; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D019205:GTP-Binding Protein alpha Subunits, Gs