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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