Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP

Nature ◽  
10.1038/24884 ◽  
1998 ◽  
Vol 396 (6710) ◽  
pp. 474-477 ◽  
Author(s):  
Johan de Rooij ◽  
Fried J. T. Zwartkruis ◽  
Mark H. G. Verheijen ◽  
Robbert H. Cool ◽  
Sebastian M. B. Nijman ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Guanine Nucleotide Exchange Factor ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor

scholarly journals The RAP1 Guanine Nucleotide Exchange Factor Epac2 Couples Cyclic AMP and Ras Signals at the Plasma Membrane

2005 ◽  
Vol 281 (5) ◽  
pp. 2506-2514 ◽  
Author(s):  
Yu Li ◽  
Sirisha Asuri ◽  
John F. Rebhun ◽  
Ariel F. Castro ◽  
Nivanka C. Paranavitana ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cyclic Amp ◽  
Guanine Nucleotide Exchange Factor ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor

scholarly journals Direct Binding of the β1 Adrenergic Receptor to the Cyclic AMP-Dependent Guanine Nucleotide Exchange Factor CNrasGEF Leads to Ras Activation

2002 ◽  
Vol 22 (22) ◽  
pp. 7942-7952 ◽  
Author(s):  
Youngshil Pak ◽  
Nam Pham ◽  
Daniela Rotin
Keyword(s):  
Cyclic Amp ◽  
Adrenergic Receptor ◽  
Pdz Domain ◽  
Guanine Nucleotide Exchange Factor ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Ras Activation

ABSTRACT G-protein-coupled receptors (GPCRs) can indirectly activate Ras primarily through the βγ 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 β1 adrenergic receptor (β1-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 β1-AR and CNrasGEF, Ras is activated by the β1-AR agonist isoproterenol, and this activation is abolished in β1-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 Gsα and not via Gβγ. In contrast to β1-AR, the β2-AR neither binds CNrasGEF nor activates Ras via CNrasGEF after agonist stimulation. These results suggest a model whereby the physical interaction between the β1-AR and CNrasGEF facilitates the transduction of Gsα-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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