scholarly journals A Novel PDZ Domain Containing Guanine Nucleotide Exchange Factor Links Heterotrimeric G Proteins to Rho

1999 ◽  
Vol 274 (9) ◽  
pp. 5868-5879 ◽  
Author(s):  
Shigetomo Fukuhara ◽  
Cristina Murga ◽  
Muriel Zohar ◽  
Tadashi Igishi ◽  
J. Silvio Gutkind
2008 ◽  
Vol 19 (9) ◽  
pp. 3638-3651 ◽  
Author(s):  
Hannah Hope ◽  
Stéphanie Bogliolo ◽  
Robert A. Arkowitz ◽  
Martine Bassilana

Rho G proteins and their regulators are critical for cytoskeleton organization and cell morphology in all eukaryotes. In the opportunistic pathogen Candida albicans, the Rho G proteins Cdc42 and Rac1 are required for the switch from budding to filamentous growth in response to different stimuli. We show that Dck1, a protein with homology to the Ced-5, Dock180, myoblast city family of guanine nucleotide exchange factors, is necessary for filamentous growth in solid media, similar to Rac1. Our results indicate that Dck1 and Rac1 do not function in the same pathway as the transcription factor Czf1, which is also required for embedded filamentous growth. The conserved catalytic region of Dck1 is required for such filamentous growth, and in vitro this region directly binds a Rac1 mutant, which mimics the nucleotide-free state. In vivo overexpression of a constitutively active Rac1 mutant, but not wild-type Rac1, in a dck1 deletion mutant restores filamentous growth. These results indicate that the Dock180 guanine nucleotide exchange factor homologue, Dck1 activates Rac1 during invasive filamentous growth. We conclude that specific exchange factors, together with the G proteins they activate, are required for morphological changes in response to different stimuli.


2002 ◽  
Vol 22 (22) ◽  
pp. 7942-7952 ◽  
Author(s):  
Youngshil Pak ◽  
Nam Pham ◽  
Daniela Rotin

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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