PathBank

Pathway Description

Succinate Signalling During Inflammation

Rattus norvegicus

Category:

Protein Pathway

Sub-Categories:

Created: 2018-09-14

Last Updated: 2019-08-16

Succinate induces calcium mobilization in an adenylyl cyclase (AC) and protein kinase A (PKA)-dependent manner. Succinate receptor 1 (SUCNR1) engagement activates phospholipase C (PLC), resulting in the cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol trisphosphate (IP3) and diacylglycerol (DAG). These second messengers induce calcium mobilization and PKC activation, respectively, and subsequent nitric oxide (NO) and prostaglandin E2 (PGE2) production as well as p38 activation. PKC-dependent phosphorylation of extracellular signal-related kinases ERK1/2 can also drive PG production. SUCNR1 signaling might act in synergy with several inflammatory signaling cascades. PKA is known to phosphorylate and activate the p65 subunit of nuclear factor κB (NF-κB) and cAMP response element-binding protein (CREB). Furthermore, NF-κB, activating protein (AP)-1, nuclear factor of activated T cells (NFAT), and ETS domain-containing protein (Elk-1) are all downstream targets of PKC and MAPKs.

References

Succinate Signalling During Inflammation References

Suh PG, Ryu SH, Moon KH, Suh HW, Rhee SG: Cloning and sequence of multiple forms of phospholipase C. Cell. 1988 Jul 15;54(2):161-9. doi: 10.1016/0092-8674(88)90548-x.

Pubmed: 3390863

Jhon DY, Lee HH, Park D, Lee CW, Lee KH, Yoo OJ, Rhee SG: Cloning, sequencing, purification, and Gq-dependent activation of phospholipase C-beta 3. J Biol Chem. 1993 Mar 25;268(9):6654-61.

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Lundby A, Secher A, Lage K, Nordsborg NB, Dmytriyev A, Lundby C, Olsen JV: Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues. Nat Commun. 2012 Jun 6;3:876. doi: 10.1038/ncomms1871.

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Hamil KG, Hall SH: Cloning of rat Sertoli cell follicle-stimulating hormone primary response complementary deoxyribonucleic acid: regulation of TSC-22 gene expression. Endocrinology. 1994 Mar;134(3):1205-12. doi: 10.1210/endo.134.3.8161377.

Pubmed: 8161377

Nemoto S, DiDonato JA, Lin A: Coordinate regulation of IkappaB kinases by mitogen-activated protein kinase kinase kinase 1 and NF-kappaB-inducing kinase. Mol Cell Biol. 1998 Dec;18(12):7336-43. doi: 10.1128/mcb.18.12.7336.

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Wooten MW, Geetha T, Seibenhener ML, Babu JR, Diaz-Meco MT, Moscat J: The p62 scaffold regulates nerve growth factor-induced NF-kappaB activation by influencing TRAF6 polyubiquitination. J Biol Chem. 2005 Oct 21;280(42):35625-9. doi: 10.1074/jbc.C500237200. Epub 2005 Aug 3.

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Saito N, Courtois G, Chiba A, Yamamoto N, Nitta T, Hironaka N, Rowe M, Yamamoto N, Yamaoka S: Two carboxyl-terminal activation regions of Epstein-Barr virus latent membrane protein 1 activate NF-kappaB through distinct signaling pathways in fibroblast cell lines. J Biol Chem. 2003 Nov 21;278(47):46565-75. doi: 10.1074/jbc.M302549200. Epub 2003 Sep 10.

Pubmed: 12968033

Nemeth E, Bole-Feysot C, Tashima LS: Suppression subtractive hybridization (SSH) identifies prolactin stimulation of p38 MAP kinase gene expression in Nb2 T lymphoma cells: molecular cloning of rat p38 MAP kinase. J Mol Endocrinol. 1998 Feb;20(1):151-6.

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Shi Y, Gaestel M: In the cellular garden of forking paths: how p38 MAPKs signal for downstream assistance. Biol Chem. 2002 Oct;383(10):1519-36. doi: 10.1515/BC.2002.173.

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Cuadrado A, Nebreda AR: Mechanisms and functions of p38 MAPK signalling. Biochem J. 2010 Aug 1;429(3):403-17. doi: 10.1042/BJ20100323.

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Saitoh F, Tian QB, Okano A, Sakagami H, Kondo H, Suzuki T: NIDD, a novel DHHC-containing protein, targets neuronal nitric-oxide synthase (nNOS) to the synaptic membrane through a PDZ-dependent interaction and regulates nNOS activity. J Biol Chem. 2004 Jul 9;279(28):29461-8. doi: 10.1074/jbc.M401471200. Epub 2004 Apr 22.

Pubmed: 15105416

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This pathway was propagated using PathWhiz - Pon, A. et al. Pathways with PathWhiz (2015) Nucleic Acids Res. 43(Web Server issue): W552–W559.

Propagated from SMP0084634

	Calcium
	DG(16:0/20:4(5Z,8Z,11Z,14Z)/0:0)
	Inositol 1,3,4-trisphosphate
	Magnesium
	Nitric oxide
	PIP2(18:1(11Z)/20:3(8Z,11Z,14Z))
	Prostaglandin E2
	Succinic acid

	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1
	Cyclic AMP-responsive element-binding protein 1
	Inhibitor of nuclear factor kappa-B kinase subunit beta
	Mitogen-activated protein kinase 1
	Mitogen-activated protein kinase 14
	Mitogen-activated protein kinase 3
	NF-kappa-B essential modulator
	Nitric oxide synthase, endothelial
	Nuclear factor NF-kappa-B p105 subunit
	Prostaglandin G/H synthase 1
	Protein kinase C alpha type
	Unknown

		Calcium
		DG(16:0/20:4(5Z,8Z,11Z,14Z)/0:0)
		Inositol 1,3,4-trisphosphate
		Magnesium
		Nitric oxide
		PIP2(18:1(11Z)/20:3(8Z,11Z,14Z))
		Prostaglandin E2
		Succinic acid

		1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1
		Cyclic AMP-responsive element-binding protein 1
		Inhibitor of nuclear factor kappa-B kinase subunit beta
		Mitogen-activated protein kinase 1
		Mitogen-activated protein kinase 14
		Mitogen-activated protein kinase 3
		NF-kappa-B essential modulator
		Nitric oxide synthase, endothelial
		Nuclear factor NF-kappa-B p105 subunit
		Prostaglandin G/H synthase 1
		Protein kinase C alpha type
		Unknown

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Succinate Signalling During Inflammation

Succinate Signalling During Inflammation References