Effects of PIP2 hydrolysis (Homo sapiens)

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Bibliography

1. van Blitterswijk WJ, Houssa B.; ''Properties and functions of diacylglycerol kinases.''; PubMed Europe PMC Scholia
2. Foskett JK, White C, Cheung KH, Mak DO.; ''Inositol trisphosphate receptor Ca2+ release channels.''; PubMed Europe PMC Scholia
3. Mellor H, Parker PJ.; ''The extended protein kinase C superfamily.''; PubMed Europe PMC Scholia
4. Newton AC.; ''Lipid activation of protein kinases.''; PubMed Europe PMC Scholia
5. Chau LY, Tai HH.; ''Release of arachidonate from diglyceride in human platelets requires the sequential action of a diglyceride lipase and a monoglyceride lipase.''; PubMed Europe PMC Scholia
6. Carrasco S, Mérida I.; ''Diacylglycerol, when simplicity becomes complex.''; PubMed Europe PMC Scholia
7. Mahaut-Smith MP, Sage SO, Rink TJ.; ''Receptor-activated single channels in intact human platelets.''; PubMed Europe PMC Scholia
8. Navia-Paldanius D, Savinainen JR, Laitinen JT.; ''Biochemical and pharmacological characterization of human α/β-hydrolase domain containing 6 (ABHD6) and 12 (ABHD12).''; PubMed Europe PMC Scholia
9. Wang J, Ueda N.; ''Biology of endocannabinoid synthesis system.''; PubMed Europe PMC Scholia
10. Riccio A, Mattei C, Kelsell RE, Medhurst AD, Calver AR, Randall AD, Davis JB, Benham CD, Pangalos MN.; ''Cloning and functional expression of human short TRP7, a candidate protein for store-operated Ca2+ influx.''; PubMed Europe PMC Scholia
11. Savinainen JR, Saario SM, Laitinen JT.; ''The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors.''; PubMed Europe PMC Scholia
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History

External references

DataNodes

Name	Type	Database reference	Comment
1,2-daG3P	Metabolite	CHEBI:29089 (ChEBI)
2AG	Metabolite	CHEBI:52392 (ChEBI)
3AG	Metabolite	CHEBI:75571 (ChEBI)
AA	Metabolite	CHEBI:15843 (ChEBI)
ABHD12	Protein	Q8N2K0 (Uniprot-TrEMBL)
ABHD6	Protein	Q9BV23 (Uniprot-TrEMBL)
ABHD6,12	Complex	R-HSA-5694453 (Reactome)
ADP	Metabolite	CHEBI:456216 (ChEBI)
ATP	Metabolite	CHEBI:30616 (ChEBI)
Ca2+	Metabolite	CHEBI:29108 (ChEBI)
Ca2+	Metabolite	CHEBI:29108 (ChEBI)
CalDAG-GEFs:DAG:Ca2+	Complex	R-HSA-392841 (Reactome)
CalDAG-GEFs	Complex	R-HSA-392488 (Reactome)	Rap1 can be activated by certain GEFs that respond to calcium and diacylglycerol (CalDAG-GEFs).
DAG	Metabolite	CHEBI:17815 (ChEBI)
DAG-activated TRPC3/6/7	Complex	R-HSA-426179 (Reactome)
DAG	Metabolite	CHEBI:17815 (ChEBI)
DAGLA	Protein	Q9Y4D2 (Uniprot-TrEMBL)
DAGLB	Protein	Q8NCG7 (Uniprot-TrEMBL)
DGKA	Protein	P23743 (Uniprot-TrEMBL)
DGKB	Protein	Q9Y6T7 (Uniprot-TrEMBL)
DGKD	Protein	Q16760 (Uniprot-TrEMBL)
DGKE	Protein	P52429 (Uniprot-TrEMBL)
DGKG	Protein	P49619 (Uniprot-TrEMBL)
DGKH	Protein	Q86XP1 (Uniprot-TrEMBL)
DGKI	Protein	O75912 (Uniprot-TrEMBL)
DGKK	Protein	Q5KSL6 (Uniprot-TrEMBL)
DGKQ	Protein	P52824 (Uniprot-TrEMBL)
DGKZ	Protein	Q13574 (Uniprot-TrEMBL)
Diacylglycerol kinase	Complex	R-HSA-426070 (Reactome)
Diacylglycerol lipase	Complex	R-HSA-426024 (Reactome)
Fatty Acid	Metabolite	CHEBI:35366 (ChEBI)
Glycerol	Metabolite	CHEBI:17754 (ChEBI)
H+	Metabolite	CHEBI:15378 (ChEBI)
H2O	Metabolite	CHEBI:15377 (ChEBI)
I(1,4,5)P3	Metabolite	CHEBI:16595 (ChEBI)
I(1,4,5)P3	Metabolite	CHEBI:16595 (ChEBI)
IP3R tetramer:I(1,4,5)P3:4xCa2+	Complex	R-HSA-139839 (Reactome)
IP3R tetramer	Complex	R-HSA-418292 (Reactome)
ITPR1	Protein	Q14643 (Uniprot-TrEMBL)
ITPR2	Protein	Q14571 (Uniprot-TrEMBL)
ITPR3	Protein	Q14573 (Uniprot-TrEMBL)
MGLL	Protein	Q99685 (Uniprot-TrEMBL)
PRKCD	Protein	Q05655 (Uniprot-TrEMBL)
PRKCE	Protein	Q02156 (Uniprot-TrEMBL)
PRKCH	Protein	P24723 (Uniprot-TrEMBL)
PRKCQ	Protein	Q04759 (Uniprot-TrEMBL)
Protein kinase C, novel isoforms:DAG	Complex	R-HSA-426071 (Reactome)
Protein kinase C, novel isoforms	Complex	R-HSA-425850 (Reactome)	These isoforms of PKC bind DAG and phosphatidylserine (PS), but unlike the conventional forms, do not require calcium for PS binding.
RASGRP1	Protein	O95267 (Uniprot-TrEMBL)
RASGRP2	Protein	Q7LDG7 (Uniprot-TrEMBL)
TRPC3(1-848)	Protein	Q13507 (Uniprot-TrEMBL)
TRPC3/6/7	Complex	R-HSA-426176 (Reactome)
TRPC6	Protein	Q9Y210 (Uniprot-TrEMBL)
TRPC7	Protein	Q9HCX4 (Uniprot-TrEMBL)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	1,2-daG3P	Arrow	R-HSA-426240 (Reactome)
	2AG	Arrow	R-HSA-426032 (Reactome)
2AG			R-HSA-426043 (Reactome)
3AG			R-HSA-5694462 (Reactome)
	AA	Arrow	R-HSA-426043 (Reactome)
	AA	Arrow	R-HSA-5694462 (Reactome)
ABHD6,12		mim-catalysis	R-HSA-5694462 (Reactome)
	ADP	Arrow	R-HSA-426240 (Reactome)
ATP			R-HSA-426240 (Reactome)
	Ca2+	Arrow	R-HSA-139854 (Reactome)
Ca2+			R-HSA-139854 (Reactome)
Ca2+			R-HSA-392831 (Reactome)
	CalDAG-GEFs:DAG:Ca2+	Arrow	R-HSA-392831 (Reactome)
CalDAG-GEFs			R-HSA-392831 (Reactome)
	DAG-activated TRPC3/6/7	Arrow	R-HSA-426209 (Reactome)
DAG			R-HSA-392831 (Reactome)
DAG			R-HSA-425861 (Reactome)
DAG			R-HSA-426032 (Reactome)
DAG			R-HSA-426209 (Reactome)
DAG			R-HSA-426240 (Reactome)
Diacylglycerol kinase		mim-catalysis	R-HSA-426240 (Reactome)
Diacylglycerol lipase		mim-catalysis	R-HSA-426032 (Reactome)
	Fatty Acid	Arrow	R-HSA-426032 (Reactome)
	Glycerol	Arrow	R-HSA-426043 (Reactome)
	Glycerol	Arrow	R-HSA-5694462 (Reactome)
	H+	Arrow	R-HSA-426043 (Reactome)
	H+	Arrow	R-HSA-5694462 (Reactome)
H2O			R-HSA-426043 (Reactome)
H2O			R-HSA-5694462 (Reactome)
I(1,4,5)P3			R-HSA-139941 (Reactome)
	IP3R tetramer:I(1,4,5)P3:4xCa2+	Arrow	R-HSA-139941 (Reactome)
IP3R tetramer:I(1,4,5)P3:4xCa2+		mim-catalysis	R-HSA-139854 (Reactome)
IP3R tetramer			R-HSA-139941 (Reactome)
MGLL		mim-catalysis	R-HSA-426043 (Reactome)
	Protein kinase C, novel isoforms:DAG	Arrow	R-HSA-425861 (Reactome)
Protein kinase C, novel isoforms			R-HSA-425861 (Reactome)
			R-HSA-139854 (Reactome)	The IP3 receptor (IP3R) is an intracellular calcium release channel that mobilizes Ca2+ from internal stores in the ER to the cytoplasm. Though its activity is stimulated by IP3, the principal activator of the IP3R is Ca2+. This process of calcium-induced calcium release is central to the mechanism of Ca2+ signalling. The effect of cytosolic Ca2+ on IP3R is complex: it can be both stimulatory and inhibitory and can the effect varies between IP3R isoforms. In general, the IP3Rs have a bell-shaped Ca2+ dependence when treated with low concentrations of IP3; low concentrations of Ca2+ (100–300 nM) are stimulatory but above 300 nM, Ca2+ becomes inhibitory and switches the channel off. The stimulatory effect of IP3 is to relieve Ca2+ inhibition of the channel, enabling Ca2+ activation sites to gate it. Functionally the IP3 receptor is believed to be tetrameric, with results indicating that the tetramer is composed of 2 pairs of protein isoforms.
			R-HSA-139941 (Reactome)	The IP3 receptor (IP3R) is an intracellular calcium release channel that mobilizes Ca2+ from internal stores in the ER to the cytoplasm. Though its activity is stimulated by IP3, the principal activator of the IP3R is Ca2+. This process of calcium-induced calcium release is central to the mechanism of Ca2+ signalling. The effect of cytosolic Ca2+ on IP3R is complex: it can be both stimulatory and inhibitory and can the effect varies between IP3R isoforms. In general, the IP3Rs have a bell-shaped Ca2+ dependence when treated with low concentrations of IP3; low concentrations of Ca2+ (100–300 nM) are stimulatory but above 300 nM, Ca2+ becomes inhibitory and switches the channel off. The stimulatory effect of IP3 is to relieve Ca2+ inhibition of the channel, enabling Ca2+ activation sites to gate it. Functionally the IP3 receptor is believed to be tetrameric, with results indicating that the tetramer is composed of 2 pairs of protein isoforms.
			R-HSA-392831 (Reactome)	Calcium and DAG regulated guanine nucleotide exchange factors (CalDAG-GEFs, also called RasGRPs) contain a regulatory C1 diacylglycerol (DAG) -binding domain analogous to the C1 domain found in Protein Kinase C, and a pair of calcium-binding EF-hand domains. All forms show enhanced activity in response to DAG and bind calcium, but the effect of Ca2+ seems to differ between isoforms. CalDAG-GEFI exhibited additive enhancement of Rap1 activation in response to Ca2+ ionophore and phorbol ester (Kawasaki et al. 1998). RasGRP2, an isofom of CalDAG-GEFI with an alternatively spliced N-terminal extension, reported to target it to the plasma membrane, was stimulated by diacylglycerol but inhibited by calcium (Clyde-Smith et al. 2000). CalDAG-GEF II/RasGRP1 was additively stimulated by Ca2+ ionophore and phorbol ester. CalDAG-GEFI was found to primarily target Rap1A and inhibit Ras-dependent activation of the Erk/MAP kinase cascade (Kawasaki et al. 1998). RasGRP2 selectively activated N- and Ki-Ras, but not Ha-Ras. It also had Rap1A stimulating activity, but less than CalDAG-GEFI. The difference in substrate specificity seen for these isoforms may be due to their different cellular locations, as prolonged exposure to phorbol esters, or growth in serum, resulted in localization of CalDAG-GEFI to the cell membrane and restoration of Ras exchange activity (Clyde-Smith et al. 2000). CalDAG-GEF II/RasGRP1 targeted Ras proteins rather than Rap (Kawasaki et al. 1998, Ebinu et al. 1998). Mouse platelets that lack CalDAG-GEFI are severely compromised in integrin-dependent aggregation as a consequence of their inability to signal through CalDAG-GEFI to its target, the small GTPase Rap1 (Crittenden et al. 2004)
			R-HSA-425861 (Reactome)	Activation of the novel Protein Kinase C (nPKC) isoforms (delta, epsilon, eta and theta) requires binding to the membrane lipid diacylglycerol (DAG). nPKC activation is sensitive to DAG concentration.
			R-HSA-426032 (Reactome)	Diacylglycerol lipase (DAGL) hydrolyzes diacylglycerol (DAG) at the sn-1 position, producing 2-monoacylglycerols, including 2-arachidonlyglycerol (2-AG) and free fatty acid. This reaction was first characterised for the release of arachidonate from membrane phospholipids in platelets, but is also involved in the spatial and temporal regulation of endocannabinoid signaling in the brain. DAGL exhibits strong selectivity for diacylglycerols over phospholipids, monoacylglycerols, triacylglycerols and fatty acid amides, and prefers the acyl group at sn-1 position to that at sn-2.
			R-HSA-426043 (Reactome)	Monoacylglycerol lipase (MAGL) is a key enzyme in the hydrolysis of the endocannabinoid 2-arachidonoylglycerol to arachidonate and glycerol. In adipocytes MAGL and hormone-sensitive lipase (LIPE) hydrolyze intracellular triglyceride stores. MAGL may also complement lipoprotein lipase (LPL) in completing hydrolysis of monoglycerides resulting from degradation of lipoprotein triglycerides.
			R-HSA-426209 (Reactome)	TRPC3, 6 and 7 are non-selective cation channels that are activated by diacylglycerol (DAG) independently of protein kinase C activation by DAG. By analogy with the structures of voltage-regulated calcium channels, TRPC channels are probably tetramers of TRPC protein; heterotetramers within the 3/6/7 group have been observed.
			R-HSA-426240 (Reactome)	Diacylglycerol kinases (DGKs) are intracellular lipid kinases that use ATP to phosphorylate diacylglycerol (DAG)., generating phosphatidic acid (PA). This lowers membrane DAG levels, regulating signalling proteins that require DAG for membrane association such as Protein Kinase C. PA is a signalling molecule that regulates Raf-1 and PKC zeta, and a substrate for the resynthesis of phosphatidylinositol.
			R-HSA-5694462 (Reactome)	Three members of the serine hydrolase family are involved in the degradation of the endocannabinoid 2-arachidonoylyglycerol (C20:4) (2AG). The major enzymatic route for 2AG inactivation is via hydrolysis, generating arachidonic acid (AA) and glycerol. Two of the serine hydrolases, monoacylglycerol lipases 6 and 12 (ABHD6 and 12), have preference for the 3-acyl isomer of arachidonoylyglycerol (3AG) although they can also hydrolyse 2AG at a lower rate (Navia-Paldanius et al. 2012, Savinainen et al. 2012).
TRPC3/6/7			R-HSA-426209 (Reactome)