Development - G-Proteins mediated regulation MAPK-ERK signaling

G-protein-mediated regulation of MAPK-ERK signaling

Guanine nucleotide binding protein (G-proteins) are heterotrimeric signaling molecules composed of three subunits, alpha, beta, and gamma, which dissociate receptor-induced exchange on the alpha subunit and beta/gamma heterodimer subunit. The G-protein-coupled receptors (GPCRs) initiate diverse downstream signaling cascades through 5 groups of G-proteins: G-protein alpha-i family, G-protein alpha-s, G-protein alpha-q/11, G-protein alpha12/13, G-protein beta/gamma. G-alpha and G- protein beta/gamma are capable of initiation of various downstream signaling pathways. One of distinct GPCR-induced intracellular Mitogen-activated protein kinase (MAPK) cascades are Extracellular signal-regulated kinases (ERK) cascade. However, each of the G-proteins seems to use a different mechanism for this purpose [1].

G-protein alpha-i induces downstream signaling via direct interaction with V-src sarcoma viral oncogene homolog (c-Src) kinase and RAP1GAP RAP1 GTPase activating protein (RAP1GAP1) protein. G-protein alpha-i stimulates kinase activity of c-Src, by binding to its catalytic domain, which leads to conformation change 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 (c-Raf)/ Mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2)/ERK pathway through phosphorylation of adaptor protein SHC transforming protein (Shc), and recruitment of adaptor protein Growth factor receptor-bound protein 2 (GRB2) and positive regulator of Son of sevenless homolog (SOS). Activation of MEK/ERK pathway leads to cell proliferation via phosphorylation of transcription factors ELK1 member of ETS oncogene family (Elk-1) and V-fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos). G-protein alpha-i activates MEK/ERK pathway via activation of RAP1GAP1. RAP1GAP1 transforms RAP1A RAP1A member of RAS oncogene family (RAP-1A) and inhibits v-raf murine sarcoma viral oncogene homolog B1 (B-Raf)/MEK/ERK pathway [2]. G-protein alpha-i inhibits activity of several Adenylate cyclases (such as Adenylate cyclase I) and decreases levels of Cyclic Adenosine 3',5'-phosphate (cAMP) in cell. As a result, they activate MEK/ERK pathway via decreasing of RAP-1A activity by Rho guanine nucleotide exchange factor 1 (ARH-GEF1), and Glia maturation factor beta (GMF) activity by Protein kinase A (PKA) [3].

Unlike G-protein alpha-i, G-protein alpha-s activates Adenylate cyclase I activity and increases cAMP level in cell. As a result, they activate MEK/ERK pathway via B-Raf, which, in turn, is activated by ARH-GEF1/RAP-1A signaling. In several cell types MEK/ERK pathway signaling is inhibited by PKA kinase via GMF [4].

A well-established signaling pathway for G-protein alpha-q/11 is activation of Phospholipase C beta (PLC-beta), which catalyzes hydrolysis of Phosphoinositide 4,5-bisphosphate (PtdIns(4,5)P2) to form Inositol 1,4,5-triphosphate (IP3) and Diacylglycerol (DAG). The IP3 released into the cytoplasm mobilizes Calcium (Ca(II)) from internal stores, whereas DAG activates protein kinase C epsilon (PKC-epsilon). PKC-epsilon induces PTK2B protein tyrosine kinase 2 beta (PYK2) activation. PYK2 phosphorylates adaptor protein Shc and stimulates protein cascade GRB2/SOS/H-RAS/c-RAF1/MEK/ERK. Free Ca(II) can activate CaM kinase II (CaMK II), which further phosphorylates and inhibits RAS-GTPase-activating protein (SynGAP) and induces MEK/ERK activation [5].

G-protein alpha-12 subunit activate B-Raf/MEK/ERK pathway via direct binding to and stimulation of RAS p21 protein activator 2 (RASA2). RASA2 hydrolyzes the GTP-bound form of Ras proteins and returns them to the GDP-bound form, thereby inhibiting such small GTPases like M-Ras and R-Ras. As a result, R-Ras is incapable of activating c-Raf-1, and M-Ras is incapable of inhibiting MR-GEF. MR-GEF activates B-Raf and inhibits c-Raf-1 via RAP-1A transformation [6].

G-protein beta/gamma subunits activate MEK/ERK pathway via activation of c-Src. c-Src activates ERK pathway through phosphorylation of Shc, and recruitment of GRB2 and SOS [7].

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