title: Regulated localization is sufficient for hormonal control of regulator of G protein signaling homology Rho guanine nucleotide exchange factors (RH-RhoGEFs).
abstract: The regulator of G protein signaling homology (RH) Rho guanine nucleotide exchange factors (RhoGEFs) (p115RhoGEF, leukemia-associated RhoGEF, and PDZ-RhoGEF) contain an RH domain and are specific GEFs for the monomeric GTPase RhoA. The RH domains interact specifically with the α subunits of G12 heterotrimeric GTPases. Activated Gα13 modestly stimulates the exchange activity of both p115RhoGEF and leukemia-associated RhoGEF but not PDZ-RhoGEF. Because all three RH-RhoGEFs can localize to the plasma membrane upon expression of activated Gα13, cellular localization of these RhoGEFs has been proposed as a mechanism for controlling their activity. We use a small molecule-regulated heterodimerization system to rapidly control the localization of RH-RhoGEFs. Acute localization of the proteins to the plasma membrane activates RhoA within minutes and to levels that are comparable with activation of RhoA by hormonal stimulation of G protein-coupled receptors. The catalytic activity of membrane-localized RhoGEFs is not dependent on activated Gα13. We further show that the conserved RH domains can rewire two different RacGEFs to activate Rac1 in response to a traditional activator of RhoA. Thus, RH domains act as independent detectors for activated Gα13 and are sufficient to modulate the activity of RhoGEFs by hormones via mediating their localization to substrate, membrane-associated RhoA.
authors.affiliation: From the Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Carter
authors.affiliation: From the Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
authors.forename: Stephen
authors.initials: S
authors.lastname: Gutowski
authors.affiliation: From the Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390 Paul.Sternweis@UTsouthwestern.edu.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Sternweis
mesh_terms: D002384:Catalysis; D002462:Cell Membrane / Q000737:chemistry / Q000201:enzymology / Q000235:genetics; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006728:Hormones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D055503:Protein Multimerization / Q000502:physiology*; D064067:Rho Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: C577234:ARHGEF11 protein, human; D006728:Hormones; D064067:Rho Guanine Nucleotide Exchange Factors; C066737:RHOA protein, human; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020742:rhoA GTP-Binding Protein
keywords: Cell Signaling; G Protein-coupled receptor (GPCR); G13; Localization; Phospholipid Vesicle; Protein Translocation; Ras Homolog Gene Family, Member A (RhoA); Regulator of G Protein Signaling (RGS); RhoGEF; Signal Transduction