The G12/13 family is probably the least well characterized subtype, partly because G12/13 coupling is difficult to determine when compared with the other subtypes which predominantly rely on assay technologies that measure intracellular calcium. The G12/13 family are best known for their involvement in the processes of cell proliferation and morphology, such as stress fiber and focal adhesion formation. Interactions with Rho guanine nucleotide exchange factors (RhoGEFs) are thought to mediate many of these processes. (Buhl et al.1995, Sugimoto et al. 2003). Activation of Rho or the regulation of events through Rho is often taken as evidence of G12/13 signaling. Receptors that are coupled with G12/13 invariably couple with one or more other G protein subtypes, usually Gq.
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Phospholipase C activation is the classical signalling route for G alpha (q) but an additional mechanism is an inhibitory interaction between G alpha (q) and phosphatidylinositol 3-kinase alpha (PI3K alpha). There are several PI3K subtypes but only the p85 alpha/p110 alpha subtype (PI3K alpha) is a G alpha (q) effector (PMID: 18515384). Activated G alpha (q) inhibits PI3K alpha directly, in a GTP-dependent manner. G alpha(q) binding of PI3K competes with Ras, a PI3K activator (PMID: 16268778).
The classical role of the G-protein beta/gamma dimer was believed to be the inactivation of the alpha subunit, Gbeta/gamma was viewed as a negative regulator of Galpha signalling. It is now known that Gbeta/gamma subunits can directly modulate many effectors, including some also regulated by G alpha.
ROCK I (alternatively called ROK ?) and ROCK II (also known as Rho kinase or ROK ?) were originally isolated as RhoA-GTP interacting proteins. The kinase domains of ROCK I and ROCK II are 92% identical, and so far there is no evidence that they phosphorylate different substrates. RhoA, RhoB, and RhoC associate with and activate ROCK but other GTP-binding proteins can be inhibitors, e.g. RhoE, Rad and Gem. PDK1 kinase promotes ROCK I activity not through phosphorylation but by blocking RhoE association. PLK1 can phosphorylate ROCK II and this enhances the effect of RhoA. Arachidonic acid can activate ROCK independently of Rho.
ARHEF1 (p115-RhoGEF), recruited to the plasma membrane by binding to GTP-bound G-protein alpha (13) (GNA13), stimulates GDP to GTP exchange on RHOA, resulting in activation of the RHOA GTPase (Chen et al. 2012).
p115-RhoGEF is a potent GTPase activating protein (GAP) for both G alpha 12 and G alpha 13 subunits. More importantly, the interaction between activated G alpha 13 (but not G alpha 12) triggers p115-RhoGEF activity. While this pathway may be important in vivo, in prostate-derived PC-3 cells RNAi mediated knockdown of p115-RhoGEF levels had no effect on the response to thrombin (Wang et al. 2004).
Leukemia-associated RhoGEF (LARG) serves as a G alpha responsive RhoGEF for G alpha 12, 13 and possibly G alpha q. G alpha 12 activity appears to depend on LARG tyrosine phosphorylation by Tec-family kinases (Suzuki et al. 2003) or FAK (Chikumi et al. 2002). The involvement of LARG may be specific to particular receptor signalling pathways; RNAi-mediated knockdown of LARG specifically inhibited thrombin signaling via PAR1 but not LPA receptors (Wang et al 2004).
When a ligand activates a G protein-coupled receptor, it induces a conformational change in the receptor (a change in shape) that allows the receptor to function as a guanine nucleotide exchange factor (GEF), stimulating the exchange of GDP for GTP on the G alpha subunit. In the traditional view of heterotrimeric protein activation, this exchange triggers the dissociation of the now active G alpha subunit from the beta:gamma dimer, initiating downstream signalling events. The G alpha subunit has intrinsic GTPase activity and will eventually hydrolyze the attached GTP to GDP, allowing reassociation with G beta:gamma. Additional GTPase-activating proteins (GAPs) stimulate the GTPase activity of G alpha, leading to more rapid termination of the transduced signal. In some cases the downstream effector may have GAP activity, helping to deactivate the pathway. This is the case for phospholipase C beta, which possesses GAP activity within its C-terminal region (Kleuss et al. 1994).
ROCKs are primarily known as downstream effectors of RHO, but they can also be activated by arachidonic acid, which binds to the pleckstrin homology domain, releasing an autoinhibitory loop within ROCK and allowing catalytic activity (Araki et al. 2001). Proteolytic cleavage at the C-terminus by caspase-3 and granzyme B also activates ROCK1 and ROCK2, causing plasma membrane blebbing during apoptosis (Coleman et al. 2001, Sebbagh et al. 2005). Multiple targets of ROCK contribute to the stabilization of actin filaments and the generation of actin-myosin contractile force.
Guanine nucleotide exchange factors (GEFs) activate GTPases by enhancing the exchange of bound GDP for GTP. Much evidence points to GEFs being critical mediators of Rho GTPase activation (Schmidt and Hall, 2002). Many GEFs are known to be highly specific for a particular GTPase, e.g. Fgd1/Cdc42 and p115RhoGEF/Rho (Hart et al., 1996, Zheng et al., 1996). Others have a broader spectrum and activate several GTPases, e.g. Vav1 for Rac, Rho, and Cdc42 (Hart et al, 1994).
The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (12/13) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008).
About 25 receptors are reported to couple to the G12/13 G protein subtype (Riobo & Manning, 2005).Direct assay methods have not identified a receptor that only couples with G12. At least one receptor (5-HT4) only couples with G13, but most other receptors are reported to couple with both G12 and G13.
The liganded receptor undergoes a conformational change, generating a signal that is propagated in a manner that is not completely understood to the the G-protein. This stimulates the exchange of GDP for GTP in the G-protein alpha subunit, activating the G-protein.
This event is negatively regulated by some Activators of G protein signaling (AGS) proteins, a class of proteins identified in yeast functional screens for proteins able to activate G protein signaling in the absence of a G protein–coupled receptor (GPCR) (Cismowski et al. 1999, Takesono et al. 1999). AGS proteins contain G protein regulatory (GPR) motifs (also referred to as the GoLoco motif) that bind and stabilize the Galpha subunit in its GDP-bound conformation (Mochizuki et al. 1996, Peterson et al. 2000, Cao et al. 2004, Blumer & Lanier 2014). Some RGS proteins similarly bind to Galpha preventing the exchange of GDP for GTP (Soundararajan et al. 2008).
The classical model of G-protein signaling suggests that the G-protein dissociates upon GPCR activation. The active alpha subunit then participates in signaling, until its intrinsic GTPase activity degrades the bound GTP to GDP. The inactive G alpha (12/13):GDP complex has much higher affinity for the G beta:gamma complex and consequently reassociates into the inactive heterotrimeric G-protein.
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DataNodes
(12/13):LARG:Plexin
B1complexes that activate
G12/13:Heterotrimeric G-protein G12/13 (active).complexes that activate
G12/13:Heterotrimeric G-protein G12/13 (inactive).complexes that
activate G12/13that activate
G12/13Annotated Interactions
(12/13):LARG:Plexin
B1complexes that activate
G12/13:Heterotrimeric G-protein G12/13 (active).complexes that activate
G12/13:Heterotrimeric G-protein G12/13 (active).complexes that activate
G12/13:Heterotrimeric G-protein G12/13 (inactive).complexes that activate
G12/13:Heterotrimeric G-protein G12/13 (inactive).complexes that activate
G12/13:Heterotrimeric G-protein G12/13 (inactive).complexes that
activate G12/13that activate
G12/13