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  The guanine nucleotide exchange factor Vav2 is a negative regulator of parathyroid hormone receptor/G(q) signaling.

Emami-Nemini, A., Gohla, A., Urlaub, H., Lohse, M. J., & Klenk, C. (2012). The guanine nucleotide exchange factor Vav2 is a negative regulator of parathyroid hormone receptor/G(q) signaling. Molecular Pharmacology, 82(2), 217-225. doi:10.1124/mol.112.078824.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000F-EF30-8 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-CA9F-3
Genre: Journal Article

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 Creators:
Emami-Nemini, A., Author
Gohla, A., Author
Urlaub, H.1, Author              
Lohse, M. J., Author
Klenk, C., Author
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1Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              

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 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 C beta-, adenylyl cyclase-, mitogen-activated protein kinase-, and beta-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 G alpha(q) but not with G alpha(s) subunits, and it competed with PTHR for coupling to G alpha(q). Consistent with its specific interaction with G alpha(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.

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Language(s): eng - English
 Dates: 2012-05-032012-08
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1124/mol.112.078824
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Title: Molecular Pharmacology
Source Genre: Journal
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Pages: - Volume / Issue: 82 (2) Sequence Number: - Start / End Page: 217 - 225 Identifier: -