Regulated localization is sufficient for hormonal control of regulator of G protein signaling homology Rho guanine nucleotide exchange factors (RH-RhoGEFs)

Angela M. Carter, Stephen Gutowski, Paul C. Sternweis

Research output: Contribution to journalArticle

6 Scopus citations

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 G 12 heterotrimeric GTPases. Activated Gα13 modestly stimulates the exchange activity of both p115RhoGEF and leukemia-associated RhoGEF but not PDZ-RhoGEF. Because all three RHRhoGEFs 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.

Original languageEnglish (US)
Pages (from-to)19737-19746
Number of pages10
JournalJournal of Biological Chemistry
Volume289
Issue number28
DOIs
StatePublished - Jul 11 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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