Regulation of p38 and JNK signaling mediated by
The G-proteins are heterotrimeric signaling molecules composed of three
subunits, alpha, beta, and gamma. Activation by ligands of G-protein
coupled receptors (GPCRs) that interact with the trimeric G-protein 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.
The GPCRs initiate diverse downstream signaling pathways by engaging
the following G-proteins: G-protein alpha-i
family, G-protein alpha-q/11,
G-protein alpha12/13, G-protein
beta/gamma. G-protein alpha and G-protein
beta/gamma subunits initiate diverse downstream signaling pathways.
Mitogen-activated protein (MAP) kinases are important mediators of signal transduction
and play a key role in the regulation of many cellular processes, such as cell growth and
proliferation, differentiation, and apoptosis. JNK and p38 MAP kinase cascades are
activated by GPCRs in response to various stress stimuli .
Activation of G-protein alpha12/13
triggers persistent activation of Jun N-terminal kinases
(JNK) . Activated G-protein
alpha-12 and -13 subunits bind the
Rho-specific guanine nucleotide exchange factors ARHGEF1 and
LARG, stimulate RhoA-dependent
transcriptional activation, and trigger activation of the
RhoA and Rho-mediated cellular responses through the
stimulation of the ROCK, MEKK1
and JNK-specific upstream kinase
G-protein alpha-q/11 subunits stimulate
the activity of p38 mitogen-activated protein kinase (p38
MAPK) in mammalian cells. The activation of p38
MAPK by G-protein alpha-q/11 is stimulated by
kinases MEK3 and MEK6. The
MEK3 and MEK6 activation by
G-protein alpha-q/11 is dependent on phospholipase C
(PLC-beta). G alpha-q/11
subunits activate PLC-beta. The latter catalyzes hydrolysis
of phosphoinositide 4,5-bisphosphate (PtdIns(4,5)P2) to form
inositol 1,4,5-triphosphate (IP3) and diacylglycerol
(DAG). DAG activates protein
kinase C epsilon (PKC-epsilon) that induces the activation
of PYK2 and, subsequently,
c-Src. c-Src phosphorylates and
activates guanine nucleotide exchange factor VAV-2 that
stimulates MEK3 in a Rac1- and
CDC42/ MEKK4-dependent manner,
and MEK6 in a RhoA/
Serine/threonine-protein kinase N1 (PRK1)/ Mitogen-activated
protein kinase kinase kinase MLT (ZAK)-dependent manner
Heterodimeric G-protein beta/gamma subunit
mediates activation of two types of stress-activated protein kinases c-Jun NH2-terminal
kinase (JNK) and p38 mitogen-activated protein kinase
(p38 MAPK) in mammalian cells.
G-protein beta/gamma induces
JNK activation mainly through
MEK4 activation that requires
RhoA, CDC42, Rac1
and kinase Btk .
JNK activation by G-protein beta/gamma is
mediated via phosphoinositide 3-kinase gamma (PI3K class
1B). The G-protein
beta/gamma heterodimers activate PI3K
gamma via recruitment of the regulatory p101 subunit (PI3K
reg class IB (p101)) and direct stimulation of the catalytic
p110 gamma subunit (PI3K cat class IB
(p110-gamma)). PI3K converts
phosphatidylinositol 4,5-biphosphate (PI(4,5)P2) to
phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3) . PI(3,4,5)P3 is a second messenger that directly
binds via pleckstrin homology (PH) domain to the Btk kinase
and activates it. Btk binds to the adaptor protein
BLNK and stimulates nucleotide exchange factor
VAV-1. Signal transduction via PI3K class 1B
to JNK involves VAV-1,
Rac1, and protein kinase PAK1
G-protein beta/gamma induces
p38 MAPK activation by kinase
MKK3 and MKK6.
G-protein beta/gamma activates
MKK3 in a Rac1- and
CDC42-dependent manner, and requires
RhoA-, Rac1-, and
CDC42 for activating MKK6.
G-protein beta/gamma induces
MKK3 and MKK6 activation that
requires tyrosine kinase Btk .
G-protein alpha-i stimulates the
activities of two stress-activated protein kinases, JNK and
p38 MAPK. G-protein alpha-i
regulates JNK activity that is dependent on small GTPases
RhoA and CDC42, their guanine
nucleotide exchange factor VAV-2, kinases
MEKK1 and MEK4 .
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