G-protein signaling - Regulation of p38 and JNK signaling mediated by G-proteins

Regulation of p38 and JNK signaling mediated by G-proteins

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 [1].

Activation of G-protein alpha12/13 triggers persistent activation of Jun N-terminal kinases (JNK) [2]. 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 MKK7 [3].

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 [4].

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 [5]. 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) [6]. 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 [7].

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 [4].

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 c-Src, PAK1, MEKK1 and MEK4 [8].

References:

1. Naor Z, Benard O, Seger R
   Activation of MAPK cascades by G-protein-coupled receptors: the case of gonadotropin-releasing hormone receptor. Trends in endocrinology and metabolism: TEM 2000 Apr;11(3):91-9
2. Dermott JM, Ha JH, Lee CH, Dhanasekaran N
   Differential regulation of Jun N-terminal kinase and p38MAP kinase by Galpha12. Oncogene 2004 Jan 8;23(1):226-32
3. Meigs TE, Juneja J, DeMarco CT, Stemmle LN, Kaplan DD, Casey PJ
   Selective uncoupling of G alpha 12 from Rho-mediated signaling. The Journal of biological chemistry 2005 May 6;280(18):18049-55
4. Yamauchi J, Tsujimoto G, Kaziro Y, Itoh H
   Parallel regulation of mitogen-activated protein kinase kinase 3 (MKK3) and MKK6 in Gq-signaling cascade. The Journal of biological chemistry 2001 Jun 29;276(26):23362-72
5. Yamauchi J, Kaziro Y, Itoh H
   Differential regulation of mitogen-activated protein kinase kinase 4 (MKK4) and 7 (MKK7) by signaling from G protein beta gamma subunit in human embryonal kidney 293 cells. The Journal of biological chemistry 1999 Jan 22;274(4):1957-65
6. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
   Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75
7. Lopez-Ilasaca M, Gutkind JS, Wetzker R
   Phosphoinositide 3-kinase gamma is a mediator of Gbetagamma-dependent Jun kinase activation. The Journal of biological chemistry 1998 Jan 30;273(5):2505-8
8. Yamauchi J, Kawano T, Nagao M, Kaziro Y, Itoh H
   G(i)-dependent activation of c-Jun N-terminal kinase in human embryonal kidney 293 cells. The Journal of biological chemistry 2000 Mar 17;275(11):7633-40