PathBank

Pathway Description

Lysophosphatidic Acid LPA2 Signalling

Bos taurus

Category:

Protein Pathway

Sub-Categories:

Immunological

Gene Regulatory

Cytokine Signaling

Cytoskeletal Signaling

Kinase Signaling

Cellular Response

Created: 2018-08-31

Last Updated: 2019-08-16

Lysophosphatidic acid (LPA) is a water-soluble phospholipid derivative and a potent signalling molecule that binds to six known lysophosphatidic acid receptors (LPARs), named LPA1-LPA6. All six receptors belong to the G protein-coupled receptor (GPCR) superfamily which initiates intracellular signalling cascades via four G protein classes differentiated by their α subunit type: Gαs, Gαi/o, Gαq/11, Gα12/13. GPCRs mediate a wide range of biological processes, including cell survival, proliferation, migration, and differentiation, vascular regulation, and cytokine release. Due to LPA's physiological importance, abnormal LPA signalling likely contributes to the pathophysiology of many diseases. LPA biosynthesis proceeds through two major pathways: (1) the conversion of lysophospholipids (e.g. LPC, LPE, LPS) into LPA via autotaxin (ATX/Enpp2) and (2) the conversion of phosphatidic acid (PA) into LPA via phospholipase A1 or A2 (PLA1/PLA2). The binding of LPA to an LPAR allosterically activates the heterotrimeric G protein by exchanging GDP for GTP at the G protein's alpha subunit. This results in the dissociation of a Gα-GTP monomer and a Gβγ dimer from the receptor which allows both complexes to begin signalling cascades via downstream effectors. LPA1 signalling has been implicated in important processes such as cell survival, proliferation, adhesion, migration, immune function, and myelination. This receptor can couple with the G proteins Gαi/o, Gαq/11, and Gα12/13. The Gαi/o subunit inhibits the enzyme adenylyl cyclase (AC) which catalyzes the production of the important secondary messenger 3',5'-cyclic AMP (cAMP) from adenosine triphosphate (ATP). Other downstream effectors of Gαi/o include the MAPK/ERK pathway, the PI3K/Akt pathway, and P13K/Rac signalling. The Gαq/11 subunit activates phospholipase C (PLC) which cleaves the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) into the secondary messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 diffuses through the cytoplasm to the ER and binds to the inositol 1,4,5-trisphosphate (Ins3P) receptor, releasing calcium from the endoplasmic reticulum into the cytoplasm. Both calcium and DAG activate the kinase activity of protein kinase C beta (PKC). Among many other functions, PKC activates NF-κB. This leads to increased antigen presentation and increased expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. The Gα12/13 subunit regulates cell motility and cytoskeletal remodelling by activating the Rho/ROCK and Rho/SRF pathways.

References

Lysophosphatidic Acid LPA2 Signalling References

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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 SMP0063753

	Adenosine triphosphate
	Calcium
	cAMP
	Guanosine diphosphate
	Guanosine triphosphate
	Inositol 1,4,5-trisphosphate
	Magnesium
	Pyrophosphate
	Water

	Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
	Inositol 1,4,5-trisphosphate receptor type 1
	Lysophosphatidic acid receptor 1
	RAC-alpha serine/threonine-protein kinase
	Rho-associated protein kinase 2
	Serum response factor

		Adenosine triphosphate
		Calcium
		cAMP
		Guanosine diphosphate
		Guanosine triphosphate
		Inositol 1,4,5-trisphosphate
		Magnesium
		Pyrophosphate
		Water

		Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
		Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
		Inositol 1,4,5-trisphosphate receptor type 1
		Lysophosphatidic acid receptor 1
		RAC-alpha serine/threonine-protein kinase
		Rho-associated protein kinase 2
		Serum response factor

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Lysophosphatidic Acid LPA2 Signalling

Lysophosphatidic Acid LPA2 Signalling References