G-protein signaling - G-Protein alpha-i signaling cascades

G-Protein alpha-i signaling cascades

Guanine nucleotide binding protein alpha inhibiting activity polypeptide 1 (G-protein alpha-i) coupled receptors interact with trimeric G-protein alpha-i/G-protein beta/gamma, which causes exchange of GDP for GTP bound to G protein alpha subunits and dissociation of G-protein beta/gamma heterodimers.

G-protein alpha-i, directly stimulates kinase activity of tyrosine-protein kinase v-src sarcoma viral oncogene homolog (c-SRC) by binding to its catalytic domain and changing conformation of c-SRC. In turn, c-SRC activates v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras)/V-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/Mitogen-activated protein kinase kinase 1 and 2 (MEK1/2)/Mitogen-activated protein kinase 1 and 3 (Erk (MAPK1/3)) pathway via phosphorylation of adaptor protein SHC transforming protein 1 (SHC) and recruitment of adaptor protein Growth factor receptor-bound protein 2 (GRB2) and positive regulator of RAS guanine nucleotide exchange protein Son of sevenless homolog (SOS), leading to cell proliferation and activation of transcription factor signal transducer and activator of transcription 3 (STAT3) [1].

G-protein alpha-i mediates activation of RAP1 GTPase activating protein (RAP1GAP1). RAP1GAP1 transforms RAP1A member of RAS oncogene family (RAP-1A) and inhibits V-raf murine sarcoma viral oncogene homolog B1 (B-RAF)/MEK1/2/Erk (MAPK1/3) pathway. [2]

G-protein alpha-i inhibits some Adenylate cyclases activity and decreases cAMP concentration in the cell [3].

Regulator of G-protein signaling (RGS) proteins are a family of proteins that have been shown to act as GTPase-activating proteins, which attenuate signaling by heterotrimeric G proteins. RGS7, RGS10, RGS11, RGS14, and RGS18 directly bind to G-protein alpha-i and selectively inhibit G protein alpha-i function [4].

Caveolin-1 interacts with G-protein alpha-i subunits and can functionally suppress their activity [5].

References:

1. Ma YC, Huang XY
   Novel regulation and function of Src tyrosine kinase. Cellular and molecular life sciences : CMLS 2002 Mar;59(3):456-62
2. Weissman JT, Ma JN, Essex A, Gao Y, Burstein ES
   G-protein-coupled receptor-mediated activation of rap GTPases: characterization of a novel Galphai regulated pathway. Oncogene 2004 Jan 8;23(1):241-9
3. Defer N, Best-Belpomme M, Hanoune J
   Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase. American journal of physiology. Renal physiology 2000 Sep;279(3):F400-16
4. Zhong H, Neubig RR
   Regulator of G protein signaling proteins: novel multifunctional drug targets. The Journal of pharmacology and experimental therapeutics 2001 Jun;297(3):837-45
5. Minshall RD, Tiruppathi C, Vogel SM, Malik AB
   Vesicle formation and trafficking in endothelial cells and regulation of endothelial barrier function. Histochemistry and cell biology 2002 Feb;117(2):105-12