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
12. Schaap D, de Widt J, van der Wal J, Vandekerckhove J, van Damme J, Gussow D, Ploegh HL, van Blitterswijk WJ, van der Bend RL.; ''Purification, cDNA-cloning and expression of human diacylglycerol kinase.''; PubMed Europe PMC Scholia
13. Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G.; ''Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol.''; PubMed Europe PMC Scholia
14. Blankman JL, Simon GM, Cravatt BF.; ''A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol.''; PubMed Europe PMC Scholia
15. Berridge MJ, Lipp P, Bootman MD.; ''The versatility and universality of calcium signalling.''; PubMed Europe PMC Scholia
16. Moriyama T, Urade R, Kito M.; ''Purification and characterization of diacylglycerol lipase from human platelets.''; PubMed Europe PMC Scholia

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External references

DataNodes

Name	Type	Database reference	Comment
1,2-diacyl-glycerol 3-phosphate		CHEBI:29089 (ChEBI)
2AG	Metabolite	CHEBI:52392 (ChEBI)
AA	Metabolite	CHEBI:15843 (ChEBI)
ADP	Metabolite	CHEBI:16761 (ChEBI)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Ca2+ [cytosol]	Metabolite	CHEBI:29108 (ChEBI)
Ca2+ [platelet dense tubular network membrane]	Metabolite	CHEBI:29108 (ChEBI)
Ca2+	Metabolite	CHEBI:29108 (ChEBI)
CalDAG-GEFs:DAG:Ca2+	Complex	REACT_24405 (Reactome)
CalDAG-GEFs	Protein	REACT_18194 (Reactome)	Rap1 can be activated by certain GEFs that respond to calcium and diacylglycerol (CalDAG-GEFs).
DAG [plasma membrane]	Metabolite	CHEBI:17815 (ChEBI)
DAG-activated TRPC3/6/7	Complex	REACT_24061 (Reactome)
DAG		CHEBI:17815 (ChEBI)
Diacylglycerol kinase	Protein	REACT_20449 (Reactome)
Diacylglycerol lipase	Protein	REACT_19676 (Reactome)
Fatty Acid		CHEBI:35366 (ChEBI)
Glycerol	Metabolite	CHEBI:17754 (ChEBI)
H+	Metabolite	CHEBI:15378 (ChEBI)
H2O	Metabolite	CHEBI:15377 (ChEBI)
I(1,4,5)P3 [platelet dense tubular network membrane]	Metabolite	CHEBI:16595 (ChEBI)
I(1,4,5)P3	Metabolite	CHEBI:16595 (ChEBI)
IP3 receptor bound to IP3 and Ca++	Complex	REACT_4346 (Reactome)
IP3 receptor	Complex	REACT_18961 (Reactome)
ITPR1 [platelet dense tubular network membrane]	Protein	Q14643 (Uniprot-TrEMBL)
ITPR2 [platelet dense tubular network membrane]	Protein	Q14571 (Uniprot-TrEMBL)
ITPR3 [platelet dense tubular network membrane]	Protein	Q14573 (Uniprot-TrEMBL)
MGLL	Protein	Q99685 (Uniprot-TrEMBL)
PRKCD(1-676) [cytosol]	Protein	Q05655 (Uniprot-TrEMBL)
PRKCE [cytosol]	Protein	Q02156 (Uniprot-TrEMBL)
PRKCH [cytosol]	Protein	P24723 (Uniprot-TrEMBL)
PRKCQ [cytosol]	Protein	Q04759 (Uniprot-TrEMBL)
Protein kinase C, novel isoforms:DAG	Complex	REACT_23271 (Reactome)
Protein kinase C, novel isoforms	Protein	REACT_22540 (Reactome)	These isoforms of PKC bind DAG and phosphatidylserine (PS), but unlike the conventional forms, do not require calcium for PS binding.
RASGRP1 [cytosol]	Protein	O95267 (Uniprot-TrEMBL)
RASGRP2 [cytosol]	Protein	Q7LDG7 (Uniprot-TrEMBL)
TRPC3(1-848) [plasma membrane]	Protein	Q13507 (Uniprot-TrEMBL)
TRPC3/6/7	Protein	REACT_23108 (Reactome)
TRPC6 [plasma membrane]	Protein	Q9Y210 (Uniprot-TrEMBL)
TRPC7 [plasma membrane]	Protein	Q9HCX4 (Uniprot-TrEMBL)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	1,2-diacyl-glycerol 3-phosphate	Arrow	REACT_19402 (Reactome)
	2AG	Arrow	REACT_19135 (Reactome)
2AG			REACT_19155 (Reactome)
	AA	Arrow	REACT_19155 (Reactome)
	ADP	Arrow	REACT_19402 (Reactome)
ATP			REACT_19402 (Reactome)
	Ca2+	Arrow	REACT_118637 (Reactome)
Ca2+			REACT_118637 (Reactome)
Ca2+			REACT_23930 (Reactome)
	CalDAG-GEFs:DAG:Ca2+	Arrow	REACT_23930 (Reactome)
CalDAG-GEFs			REACT_23930 (Reactome)
	DAG-activated TRPC3/6/7	Arrow	REACT_24007 (Reactome)
DAG			REACT_19135 (Reactome)
DAG			REACT_19402 (Reactome)
DAG			REACT_23917 (Reactome)
DAG			REACT_23930 (Reactome)
DAG			REACT_24007 (Reactome)
Diacylglycerol kinase		mim-catalysis	REACT_19402 (Reactome)
Diacylglycerol lipase		mim-catalysis	REACT_19135 (Reactome)
	Fatty Acid	Arrow	REACT_19135 (Reactome)
	Glycerol	Arrow	REACT_19155 (Reactome)
	H+	Arrow	REACT_19155 (Reactome)
H2O			REACT_19155 (Reactome)
I(1,4,5)P3			REACT_1144 (Reactome)
	IP3 receptor bound to IP3 and Ca++	Arrow	REACT_1144 (Reactome)
IP3 receptor bound to IP3 and Ca++		mim-catalysis	REACT_118637 (Reactome)
IP3 receptor			REACT_1144 (Reactome)
MGLL		mim-catalysis	REACT_19155 (Reactome)
	Protein kinase C, novel isoforms:DAG	Arrow	REACT_23917 (Reactome)
Protein kinase C, novel isoforms			REACT_23917 (Reactome)
			REACT_1144 (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.
			REACT_118637 (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.
			REACT_19135 (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.
			REACT_19155 (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.
			REACT_19402 (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.
			REACT_23917 (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.
			REACT_23930 (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)
			REACT_24007 (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.
TRPC3/6/7			REACT_24007 (Reactome)