title: The guanine nucleotide exchange factor Vav2 is a negative regulator of parathyroid hormone receptor/Gq signaling.
abstract: The parathyroid hormone receptor (PTHR) is a class B G protein-coupled receptor (GPCR) that mediates the endocrine and paracrine effects of parathyroid hormone and related peptides through the activation of phospholipase Cβ-, adenylyl cyclase-, mitogen-activated protein kinase-, and β-arrestin-initiated signaling pathways. It is currently not clear how specificity among these downstream signaling pathways is achieved. A possible mechanism involves adaptor proteins that affect receptor/effector coupling. In a proteomic screen with the PTHR C terminus, we identified vav2, a guanine nucleotide exchange factor (GEF) for Rho GTPases, as a PTHR-interacting protein. The core domains of vav2 bound to the intracellular domains of the PTHR independent of receptor activation. In addition, vav2 specifically interacted with activated Gα(q) but not with Gα(s) subunits, and it competed with PTHR for coupling to Gα(q). Consistent with its specific interaction with Gα(q), vav2 impaired G(q)-mediated inositol phosphate generation but not G(s)-mediated cAMP generation. This inhibition of G(q) signaling was specific for PTHR signaling, compared with other G(q)-coupled GPCRs. Moreover, the benefit for PTHR-mediated inositol phosphate generation in the absence of vav2 required the ezrin binding domain of Na(+)/H(+)-exchanger regulatory factor 1. Our results show that a RhoA GEF can specifically interact with a GPCR and modulate its G protein signaling specificity.
authors.affiliation: Institute of Pharmacology and Toxicology, Rudolf Virchow Center, University of Würzburg, Versbacher Straße 9, Würzburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Emami-Nemini
authors.forename: Antje
authors.initials: A
authors.lastname: Gohla
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lohse
authors.forename: Christoph
authors.initials: C
authors.lastname: Klenk
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000502:physiology; D019556:COS Cells; D002522:Chlorocebus aethiops; D015536:Down-Regulation / Q000502:physiology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007294:Inositol / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism / Q000502:physiology*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D051567:Proto-Oncogene Proteins c-vav; D044168:Receptor, Parathyroid Hormone, Type 1; C093651:VAV2 protein, human; D007294:Inositol; D043802:GTP-Binding Protein alpha Subunits, Gq-G11