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Gastrin-stimulated Gα<inf>13</inf> activation of Rgnef protein (ArhGEF28) in DLD-1 colon carcinoma cells

AuthorsMasià-Balagué, Miriam ; Izquierdo, Ismael ; Garrido, Georgina ; Cordomí, Arnau; Pérez-Benito, Laura; Miller, Nichol L.G.; Schlaepfer, David D.; Gigoix, Véronique; Aragay, Anna M.
Keywordscell signaling
G protein-coupled receptor (GPCR)
guanine nucleotide exchange factor (GEF)
heterotrimeric G protein
regulator of G protein signaling
Issue Date12-Jun-2015
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Biological Chemistry 290(24): 15197-15209 (2015)
Abstract© 2015 by The American Society for Biochemistry and Molecular Biology, Inc. The guanine nucleotide exchange factor Rgnef (also known as ArhGEF28 or p190RhoGEF) promotes colon carcinoma cell motility and tumor progression via interaction with focal adhesion kinase (FAK). Mechanisms of Rgnef activation downstream of integrin or Gprotein-coupled receptors remain undefined. In the absence of a recognized G protein signaling homology domain in Rgnef, no proximal linkage to G proteins was known. Utilizing multiple methods, we have identified Rgnef as a new effector for Gα<inf>13</inf> downstream of gastrin and the type 2 cholecystokinin receptor. In DLD-1 colon carcinoma cells depleted of Gα<inf>13</inf>, gastrin-induced FAK Tyr(P)-397 and paxillin Tyr(P)-31 phosphorylation were reduced. RhoA GTP binding and promoter activity were increased by Rgnef in combination with active Gα<inf>13</inf>. Rgnef co-immunoprecipitated with activated Gα<inf>13</inf>Q226L but not Gα<inf>12</inf>Q229L. The Rgnef C-terminal (CT, 1279-1582) region was sufficient for co-immunoprecipitation, and Rgnef-CT exogenous expression prevented Gα<inf>13</inf>-stimulated SRE activity. A domain at the C terminus of the protein close to the FAK binding domain is necessary to bind to Gα<inf>13</inf>. Point mutations of Rgnef-CT residues disrupt association with active Gα<inf>13</inf> but not Gα<inf>q</inf>. These results show that Rgnef functions as an effector of Gα<inf>13</inf> signaling and that this linkage may mediate FAK activation in DLD-1 colon carcinoma cells.
Publisher version (URL)http://dx.doi.org/10.1074/jbc.M114.628164
Identifiersdoi: 10.1074/jbc.M114.628164
issn: 1083-351X
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