title: PDZ-RhoGEF and LARG are essential for embryonic development and provide a link between thrombin and LPA receptors and Rho activation.
abstract: G protein-coupled receptors (GPCRs) linked to both members of the Gα12 family of heterotrimeric G proteins α subunits, Gα12 and Gα13, regulate the activation of Rho GTPases, thereby contributing to many key biological processes. Multiple Rho GEFs have been proposed to link Gα12/13 GPCRs to Rho activation, including PDZ-RhoGEF (PRG), leukemia-associated Rho GEF (LARG), p115-RhoGEF (p115), lymphoid blast crisis (Lbc), and Dbl. PRG, LARG, and p115 share the presence of a regulator of G protein signaling homology (RGS) domain. There is limited information on the biological roles of this RGS-containing family of RhoGEFs in vivo. p115-deficient mice are viable with some defects in the immune system and gastrointestinal motor dysfunctions, whereas in an initial study we showed that mice deficient for Larg are viable and resistant to salt-induced hypertension. Here, we generated knock-out mice for Prg and observed that these mice do not display any overt phenotype. However, deficiency in Prg and Larg leads to complex developmental defects and early embryonic lethality. Signaling from Gα11/q-linked GPCRs to Rho was not impaired in mouse embryonic fibroblasts defective in all three RGS-containing RhoGEFs. However, a combined lack of Prg, Larg, and p115 expression abolished signaling through Gα12/13 to Rho and thrombin-induced cell proliferation, directional migration, and nuclear signaling through JNK and p38. These findings provide evidence of an essential role for the RGS-containing RhoGEF family in signaling to Rho by Gα12/13-coupled GPCRs, which may likely play a critical role during embryonic development.
authors: Oral and Pharyngeal Cancer Branch, NIDCR, Genetics and Developmental Biology Center, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Constantinos M
authors: CM
authors: Mikelis
authors: Todd R
authors: TR
authors: Palmby
authors: May
authors: M
authors: Simaan
authors: Wenling
authors: W
authors: Li
authors: Roman
authors: R
authors: Szabo
authors: Ruth
authors: R
authors: Lyons
authors: Daniel
authors: D
authors: Martin
authors: Hiroshi
authors: H
authors: Yagi
authors: Shigetomo
authors: S
authors: Fukuhara
authors: Hiroki
authors: H
authors: Chikumi
authors: Rebeca
authors: R
authors: Galisteo
authors: Yoh-Suke
authors: YS
authors: Mukouyama
authors: Thomas H
authors: TH
authors: Bugge
authors: J Silvio
authors: JS
authors: Gutkind
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000378:metabolism*; D047108:Embryonic Development / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000235:genetics / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C576600:ARHGEF1 protein, human; C577223:Arhgef12 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D049368:Receptors, Lysophosphatidic Acid; D018179:Receptors, Thrombin; D064067:Rho Guanine Nucleotide Exchange Factors; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020741:rho GTP-Binding Proteins