Signalling mechanisms of RhoGTPase regulation by the heterotrimeric G proteins G12 and G13

Abstract

G protein-mediated signal transduction can transduce signals from a large variety of extracellular stimuli into cells and is the most widely used mechanism for cell communication at the membrane. The RhoGTPase family has been well established as key regulators of cell growth, differentiation and cell shape changes. Among G protein-mediated signal transduction, G12/13-mediated signalling is one mechanism to regulate RhoGTPase activity in response to extracellular stimuli. The alpha subunits of G12 or G13 have been shown to interact with members of the RH domain containing guanine nucleotide exchange factors for Rho (RH-RhoGEF) family of proteins to directly connect G protein-mediated signalling and RhoGTPase signalling. The G12/13-RH-RhoGEF signalling mechanism is well conserved over species and is involved in critical steps for cell physiology and disease conditions, including embryonic development, oncogenesis and cancer metastasis. In this review, we will summarize current progress on this important signalling mechanism.

EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling

“…Moreover, TGF-β1 signaling may also regulate MMP-2 transcription (59), as reduced transcription of MMP-2 was detected in Ep3 -/-PASMCs. Interestingly, blockade of G α12 downstream ROCK (60) or knockdown of G α12 reduced the exaggerated MMP-2 activation caused by overexpression of Ep3a/b in PASMCs, further supporting the idea that the Ep3a/b-triggered MMP-2/TGF-β1 cascade collagen I ( Figure 11G) in mPASMCs caused by Ep3a/b overexpression under hypoxic stimulatory conditions. However, we did not observe a significant effect of G α13 silencing on EP3-mediated TGF-β1 signaling (Supplemental Figure 16).…”

FTY720 Phosphate Activates Sphingosine-1-Phosphate Receptor 2 and Selectively Couples to Gα12/13/Rho/ROCK to Induce Myofibroblast Contraction

“…In most cases, ligands induced at least one additional pathway, such as calcium release (Rajagopal et al, 2010;Kozasa et al, 2011), as was also seen here for the natural ligand S1P at recombinant S1P 2 receptors. Taken together, the use of the impedance-based assay technology in addition to classic GPCR assays allowed us to achieve a more complete description of compound activities at recombinant and endogenous S1P 2 receptors.…”

“…Although the activation of the Ga 12/13 /Rho/ROCK pathway is more difficult to measure than second messenger-generating pathways, its physiologic and pathophysiological importance is nevertheless high. Rho/ROCK signaling results in cellular responses, including modulation of gene transcription, rearrangement of the myosin-actin cytoskeleton, cell contraction, and fibrosis (Siehler, 2009;Kozasa et al, 2011;Knipe et al, 2015). S1P is a well established activator of the Rho/ROCK signaling pathway and is linked to multiple phenotypic changes in fibroblasts and vascular smooth muscle cells (Hu et al, 2006;Siehler, 2009;Xiang et al, 2013).…”

“…Upon agonist binding, GPCRs transmit extracellular signals to the inside of cells through activation of one or several intracellular heterotrimeric G protein subtypes to modulate cAMP levels (Ga s or Ga i proteins), increase calcium levels (Ga q proteins), or activate RhoGTPase/Rhoassociated kinases (ROCK1/2) (Ga 12/13 proteins), the latter resulting in cellular responses that include gene transcription, rearrangement of the actin cytoskeleton, and cellular shape changes (Siehler, 2009;Kozasa et al, 2011;Zhang and Xie, 2012).…”

Mouse Macrophages Completely Lacking Rho Subfamily GTPases (RhoA, RhoB, and RhoC) Have Severe Lamellipodial Retraction Defects, but Robust Chemotactic Navigation and Altered Motility

“…The G 12/13 subfamily of heterotrimeric G proteins triggers activation of RhoGEFs (Rho-specific guanine nucleotide exchange factors) (23)(24)(25), such as Lsc (human homolog, p115-RhoGEF), leukemia-associated RhoGEF, and PDZ-RhoGEF, which specifically activate the Rho subfamily. Thus, the following signaling scheme may be important for motility and chemotaxis: chemoattractant agonist 3 GPCRs 3 G 12/13 3 RhoGEFs 3 Rho subfamily GTPases (RhoA, RhoB, and RhoC) 3 effectors.…”