Modular architecture and novel protein-protein interactions regulating the RGS-containing Rho guanine nucleotide exchange factors.
The regulator of G-protein signaling (RGS)-containing RhoGEFs, including p115RhoGEF, PDZ-RhoGEF, and LARG, represent a novel family of guanine nucleotide exchange factors for RhoA that are regulated by the Galpha(12/13) family of heterotrimeric G proteins. Experimental evidence indicates that the complex architecture of these RhoGEFs provides the structural basis for novel regulatory mechanisms mediated by protein-protein interactions. These include the direct association of their RGS domain with GTP-bound forms of Galpha(12/13) and the binding of the PDZ domain present in PDZ-RhoGEF and LARG to plexins, which are receptors for semaphorins. The carboxyl-terminal region of these GEFs also exerts regulatory properties, including the ability to form dimers, which is inhibitory to their in vivo GEF activity and, in the case of PDZ-RhoGEF, to associate with PAK4, a downstream target of Cdc42. This carboxyl-terminal region also acts as the target for tyrosine kinases, which have a positive effect on the long-term activity of these GEFs. This article describes the experimental strategies that have been utilized to begin unraveling the molecular mechanisms regulating the functional activity of RGS-containing RhoGEFs.
Department of Pharmacology, CINVESTAV-IPN, México, DF, Mexico.
José
J
Vázquez-Prado
John
J
Basile
J Silvio
JS
Gutkind
D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D003599:Cytoskeleton / Q000378:metabolism; D004789:Enzyme Activation; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010590:Phalloidine / Q000031:analogs & derivatives; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D012235:Rhodamines / Q000378:metabolism; D015290:Second Messenger Systems / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D020662:Guanine Nucleotide Exchange Factors; D011993:Recombinant Fusion Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D012235:Rhodamines; D014157:Transcription Factors; D010590:Phalloidine; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020742:rhoA GTP-Binding Protein