Suppression of RhoG activity is mediated by a syndecan 4-synectin-RhoGDI1 complex and is reversed by PKCalpha in a Rac1 activation pathway.
Fibroblast growth factor 2 (FGF2) is a major regulator of developmental, pathological, and therapeutic angiogenesis. Its activity is partially mediated by binding to syndecan 4 (S4), a proteoglycan receptor. Angiogenesis requires polarized activation of the small guanosine triphosphatase Rac1, which involves localized dissociation from RhoGDI1 and association with the plasma membrane. Previous work has shown that genetic deletion of S4 or its adapter, synectin, leads to depolarized Rac activation, decreased endothelial migration, and other physiological defects. In this study, we show that Rac1 activation downstream of S4 is mediated by the RhoG activation pathway. RhoG is maintained in an inactive state by RhoGDI1, which is found in a ternary complex with synectin and S4. Binding of S4 to synectin increases the latter's binding to RhoGDI1, which in turn enhances RhoGDI1's affinity for RhoG. S4 clustering activates PKCalpha, which phosphorylates RhoGDI1 at Ser(96). This phosphorylation triggers release of RhoG, leading to polarized activation of Rac1. Thus, FGF2-induced Rac1 activation depends on the suppression of RhoG by a previously uncharacterized ternary S4-synectin-RhoGDI1 protein complex and activation via PKCalpha.
Elfenbein
Arye
A
Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, Japan.
Rhodes
John M
JM
Meller
Julia
J
Schwartz
Martin A
MA
Matsuda
Michiyuki
M
Simons
Michael
M
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D016000:Cluster Analysis; D004789:Enzyme Activation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors*; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D051381:Rats; D053671:Syndecan-4 / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020741:rho GTP-Binding Proteins; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
D002352:Carrier Proteins; D020730:Guanine Nucleotide Dissociation Inhibitors; C489577:Rhog protein, mouse; C489578:Rhog protein, rat; D053671:Syndecan-4; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D016222:Fibroblast Growth Factor 2; D010768:Phosphoserine; D051571:Protein Kinase C-alpha; D020558:GTP Phosphohydrolases; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins