1. Academic Validation
  2. Direct binding of the beta1 adrenergic receptor to the cyclic AMP-dependent guanine nucleotide exchange factor CNrasGEF leads to Ras activation

Direct binding of the beta1 adrenergic receptor to the cyclic AMP-dependent guanine nucleotide exchange factor CNrasGEF leads to Ras activation

  • Mol Cell Biol. 2002 Nov;22(22):7942-52. doi: 10.1128/MCB.22.22.7942-7952.2002.
Youngshil Pak 1 Nam Pham Daniela Rotin
Affiliations

Affiliation

  • 1 Program in Cell Biology, The Hospital for Sick Children, and Biochemistry Department, University of Toronto, Toronto, M5G 1X8 Ontario, Canada.
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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