ArticleMolecular and cellular biology2002
Direct binding of the beta1 adrenergic receptor to the cyclic AMP-dependent guanine nucleotide exchange factor CNrasGEF leads to Ras activation.
Article in Molecular and cellular biology, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 67 citations in OpenAlex.
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- Separate cyclic AMP sensors for neuritogenesis, growth arrest, and survival of neuroendocrine cells.The Journal of biological chemistry · 2014Article
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- Rapgef2 connects GPCR-mediated cAMP signals to ERK activation in neuronal and endocrine cells.Science signaling · 2013Article
- Regulation of GPCR activity, trafficking and localization by GPCR-interacting proteins.British journal of pharmacology · 2012Review
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- Protein kinase A and B-Raf mediate extracellular signal-regulated kinase activation by thyrotropin.Molecular pharmacology · 2009Article
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- A novel Dictyostelium RasGEF required for chemotaxis and development.BMC cell biology · 2005Article
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- Requirement of the Caenorhabditis elegans RapGEF pxf-1 and rap-1 for epithelial integrity.Molecular biology of the cell · 2005Article
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
G-protein-coupled receptors (GPCRs) can indirectly activate Ras primarily through the betagamma subunits of G proteins, which recruit c-Src, phosphatidylinositol 3-kinase, and Grb2-SOS. However, a direct interaction between a Ras activator (guanine nucleotide exchange factor [GEF]) and GPCRs that leads to Ras activation has never been demonstrated. We report here a novel mechanism for a direct GPCR-mediated Ras activation. The beta1 adrenergic receptor (beta1-AR) binds to the PDZ domain of the cyclic AMP (cAMP)-dependent Ras exchange factor, CNrasGEF, via its C-terminal SkV motif. In cells heterologously expressing beta1-AR and CNrasGEF, Ras is activated by the beta1-AR agonist isoproterenol, and this activation is abolished in beta1-AR mutants that cannot bind CNrasGEF or in CNrasGEF mutants lacking the catalytic CDC25 domain or cAMP-binding domain. Moreover, the activation is transduced via Gsalpha and not via Gbetagamma. In contrast to beta1-AR, the beta2-AR neither binds CNrasGEF nor activates Ras via CNrasGEF after agonist stimulation. These results suggest a model whereby the physical interaction between the beta1-AR and CNrasGEF facilitates the transduction of Gsalpha-induced cAMP signal into the activation of Ras. The present study provides the first demonstration of direct physical association between a Ras activator and a GPCR, leading to agonist-induced Ras activation
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