G-protein signaling - G-Protein alpha-12 signaling pathway

G-protein alpha-12 family signaling

Activation by ligands of G-protein coupled receptors that interact with the trimeric G-protein alpha-12/beta/gamma causes the exchange of GDP for GTP bound to G protein alpha subunits followed by dissociation of the beta/gamma heterodimers. Free alpha and beta/gamma subunits are active and transmit signals into the cells.

G-protein alpha-12 family subunits transduce signals from G protein-coupled receptors to activate Rho GTPases in the cells. G-protein alpha-12 family subunits interact with guanine nucleotide exchange factors (GEFs) ARHGEF1, Leukemia-associated RhoGEF (LARG) and ARHGEF11 and activate them. These GEFs in turn activate small GTPase Ras homolog gene family member A (RhoA) by catalyzing the RhoA conversion from GDP-bound inactive form to GTP-bound active form.

Subunits of the G-protein alpha-12 family proteins also form complexes with A-kinase anchor protein 13 (LBC) and induce signaling pathways to small GTPases RhoA, CDC42, and Rac1 [1].

RhoA or Rac1/CDC42 activate LIM kinase (LIMK) via respective effector kinases ROCK or PAK1 and inhibit the axon growth and regulation of cytoskeletal structure by affecting the structure of the actin and tubulin cytoskeletons. Rac1 and CDC42 activate mitogen-activated protein kinase (MAPK) cascades via MEKK1 and MEK4 [2].

LBC functions as a Protein kinase A (PKA)-targeting protein. PKA holoenzyme binds to LBC and phosphorylates this anchoring protein. This phosphorylation event induces the recruitment of the 14-3-3 protein that inhibits the Rho-GEF activity of LBC [3].

G-protein alpha-12 family subunits directly bind to and stimulate Ras GTPase-activating protein (RASA2). RASA2 hydrolyzes the bound GTP of the small GTP-bound GTPase to produce the GDP-bound form of the protein. This conversion inhibits small GTPases M-Ras, R-Ras and TC21 [4]. TC21 mediates transformation and cell survival via activation of Phosphatidylinositol 3-kinase (PI3K)/ v-AKT murine thymoma viral oncogene homolog (AKT)/ Nuclear factor kappaB (NF-kB) signaling pathway [5]. Activated M-Ras inhibits the ability of MR-GEF to promote RAP-1A activation, and subsequent c-Raf-1 inhibition by RAP-1A [6]. R-Ras is implicated in regulation of various cell functions, such as gene expression and cell proliferation via the activation of the c-Raf-1/ Mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2)/ Mitogen-activated protein kinases 1 and 3 (ERK1/2) signaling pathway [7].

Subunits of the G-protein alpha-12 family proteins bind directly to and stimulate the activity of Bruton's tyrosine kinase (Btk). Btk, in turn, activates PLC gamma.

Phospholipase C epsilon (PLC-epsilon) is stimulated selectively by the constitutively active form of the G-protein alpha-12 family subunits. Phospholipase C gamma (PLC-gamma), and PLC-epsilon catalyze the hydrolysis of Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to generate the second messengers Inositol 1,4,5 trisphosphate (IP3) and Diacylglycerol (DAG). This causes a cascade of intracellular responses [8].

References:

1. Dutt P, Nguyen N, Toksoz D
   Role of Lbc RhoGEF in Galpha12/13-induced signals to Rho GTPase. Cellular signalling 2004 Feb;16(2):201-9
2. Hofmann C, Shepelev M, Chernoff J
   The genetics of Pak. Journal of cell science 2004 Sep 1;117(Pt 19):4343-54
3. Diviani D, Abuin L, Cotecchia S, Pansier L
   Anchoring of both PKA and 14-3-3 inhibits the Rho-GEF activity of the AKAP-Lbc signaling complex. The EMBO journal 2004 Jul 21;23(14):2811-20
4. Ohba Y, Mochizuki N, Yamashita S, Chan AM, Schrader JW, Hattori S, Nagashima K, Matsuda M
   Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3. The Journal of biological chemistry 2000 Jun 30;275(26):20020-6
5. Rong R, He Q, Liu Y, Sheikh MS, Huang Y
   TC21 mediates transformation and cell survival via activation of phosphatidylinositol 3-kinase/Akt and NF-kappaB signaling pathway. Oncogene 2002 Feb 7;21(7):1062-70
6. Rebhun JF, Castro AF, Quilliam LA
   Identification of guanine nucleotide exchange factors (GEFs) for the Rap1 GTPase. Regulation of MR-GEF by M-Ras-GTP interaction. The Journal of biological chemistry 2000 Nov 10;275(45):34901-8
7. Guerrero C, Martin-Encabo S, Fernandez-Medarde A, Santos E
   C3G-mediated suppression of oncogene-induced focus formation in fibroblasts involves inhibition of ERK activation, cyclin A expression and alterations of anchorage-independent growth. Oncogene 2004 Jun 17;23(28):4885-93
8. Lopez I, Mak EC, Ding J, Hamm HE, Lomasney JW
   A novel bifunctional phospholipase c that is regulated by Galpha 12 and stimulates the Ras/mitogen-activated protein kinase pathway. The Journal of biological chemistry 2001 Jan 26;276(4):2758-65