Effects of PIP2 hydrolysis (Homo sapiens)

From WikiPathways

Jump to: navigation, search



Curation Tags

Description

Hydrolysis of phosphatidyl inositol-bisphosphate (PIP2) by phospholipase C (PLC) produces diacylglycerol (DAG) and inositol triphosphate (IP3). Both are potent second messengers. IP3 diffuses into the cytosol, but as DAG is a hydrophobic lipid it remains within the plasma membrane. IP3 stimulates the release of calcium ions from the smooth endoplasmic reticulum, while DAG activates the conventional and unconventional protein kinase C (PKC) isoforms, facilitating the translocation of PKC from the cytosol to the plasma membrane. The effects of DAG are mimicked by tumor-promoting phorbol esters. DAG is also a precursor for the biosynthesis of prostaglandins, the endocannabinoid 2-arachidonoylglycerol and an activator of a subfamily of TRP-C (Transient Receptor Potential Canonical) cation channels 3, 6, and 7. View original pathway at:Reactome.

Comments

Reactome Converter 
Pathway is converted from Reactome id:

Ontology Tags

 

Bibliography

View all...
  1. Berridge MJ, Lipp P, Bootman MD.; ''The versatility and universality of calcium signalling.''; PubMed
  2. Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G.; ''Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol.''; PubMed
  3. 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
  4. Carrasco S, Mérida I.; ''Diacylglycerol, when simplicity becomes complex.''; PubMed
  5. van Blitterswijk WJ, Houssa B.; ''Properties and functions of diacylglycerol kinases.''; PubMed
  6. Foskett JK, White C, Cheung KH, Mak DO.; ''Inositol trisphosphate receptor Ca2+ release channels.''; PubMed
  7. Wang J, Ueda N.; ''Biology of endocannabinoid synthesis system.''; PubMed
  8. Savinainen JR, Saario SM, Laitinen JT.; ''The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors.''; PubMed
  9. Mahaut-Smith MP, Sage SO, Rink TJ.; ''Receptor-activated single channels in intact human platelets.''; PubMed
  10. Navia-Paldanius D, Savinainen JR, Laitinen JT.; ''Biochemical and pharmacological characterization of human α/β-hydrolase domain containing 6 (ABHD6) and 12 (ABHD12).''; PubMed
  11. Mellor H, Parker PJ.; ''The extended protein kinase C superfamily.''; PubMed
  12. Moriyama T, Urade R, Kito M.; ''Purification and characterization of diacylglycerol lipase from human platelets.''; PubMed
  13. Blankman JL, Simon GM, Cravatt BF.; ''A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol.''; PubMed
  14. 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
  15. 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
  16. Newton AC.; ''Lipid activation of protein kinases.''; PubMed

History

View all...
CompareRevisionActionTimeUserComment
87436view13:35, 22 July 2016MkutmonOntology Term : 'hemostasis pathway' added !
87435view13:35, 22 July 2016MkutmonOntology Term : 'signaling pathway' added !
86547view09:20, 11 July 2016ReactomeTeamreactome version 56
83152view10:10, 18 November 2015ReactomeTeamVersion54
81503view13:02, 21 August 2015ReactomeTeamVersion53
76979view08:26, 17 July 2014ReactomeTeamFixed remaining interactions
76684view12:05, 16 July 2014ReactomeTeamFixed remaining interactions
76011view10:07, 11 June 2014ReactomeTeamRe-fixing comment source
75719view11:08, 10 June 2014ReactomeTeamReactome 48 Update
75071view13:58, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74716view08:47, 30 April 2014ReactomeTeamReactome46
42032view21:51, 4 March 2011MaintBotAutomatic update
39835view05:52, 21 January 2011MaintBotNew pathway

External references

Datanodes

View all...
NameTypeDatabase referenceComment
1,2-daG3PMetaboliteCHEBI:29089 (ChEBI)
2AGMetaboliteCHEBI:52392 (ChEBI)
3AGMetaboliteCHEBI:75571 (ChEBI)
AAMetaboliteCHEBI:15843 (ChEBI)
ABHD12 ProteinQ8N2K0 (Uniprot-TrEMBL)
ABHD6 ProteinQ9BV23 (Uniprot-TrEMBL)
ABHD6,12ComplexR-HSA-5694453 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
CalDAG-GEFs:DAG:Ca2+ComplexR-HSA-392841 (Reactome)
CalDAG-GEFsComplexR-HSA-392488 (Reactome) Rap1 can be activated by certain GEFs that respond to calcium and diacylglycerol (CalDAG-GEFs).
DAG MetaboliteCHEBI:17815 (ChEBI)
DAG-activated TRPC3/6/7ComplexR-HSA-426179 (Reactome)
DAGMetaboliteCHEBI:17815 (ChEBI)
DAGLA ProteinQ9Y4D2 (Uniprot-TrEMBL)
DAGLB ProteinQ8NCG7 (Uniprot-TrEMBL)
DGKA ProteinP23743 (Uniprot-TrEMBL)
DGKB ProteinQ9Y6T7 (Uniprot-TrEMBL)
DGKD ProteinQ16760 (Uniprot-TrEMBL)
DGKE ProteinP52429 (Uniprot-TrEMBL)
DGKG ProteinP49619 (Uniprot-TrEMBL)
DGKH ProteinQ86XP1 (Uniprot-TrEMBL)
DGKI ProteinO75912 (Uniprot-TrEMBL)
DGKK ProteinQ5KSL6 (Uniprot-TrEMBL)
DGKQ ProteinP52824 (Uniprot-TrEMBL)
DGKZ ProteinQ13574 (Uniprot-TrEMBL)
Diacylglycerol kinaseComplexR-HSA-426070 (Reactome)
Diacylglycerol lipaseComplexR-HSA-426024 (Reactome)
Fatty AcidMetaboliteCHEBI:35366 (ChEBI)
GlycerolMetaboliteCHEBI:17754 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
I(1,4,5)P3 MetaboliteCHEBI:16595 (ChEBI)
I(1,4,5)P3MetaboliteCHEBI:16595 (ChEBI)
IP3R tetramer:I(1,4,5)P3:4xCa2+ComplexR-HSA-139839 (Reactome)
IP3R tetramerComplexR-HSA-418292 (Reactome)
ITPR1 ProteinQ14643 (Uniprot-TrEMBL)
ITPR2 ProteinQ14571 (Uniprot-TrEMBL)
ITPR3 ProteinQ14573 (Uniprot-TrEMBL)
MGLLProteinQ99685 (Uniprot-TrEMBL)
PRKCD ProteinQ05655 (Uniprot-TrEMBL)
PRKCE ProteinQ02156 (Uniprot-TrEMBL)
PRKCH ProteinP24723 (Uniprot-TrEMBL)
PRKCQ ProteinQ04759 (Uniprot-TrEMBL)
Protein kinase C, novel isoforms:DAGComplexR-HSA-426071 (Reactome)
Protein kinase C, novel isoformsComplexR-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 ProteinO95267 (Uniprot-TrEMBL)
RASGRP2 ProteinQ7LDG7 (Uniprot-TrEMBL)
TRPC3(1-848) ProteinQ13507 (Uniprot-TrEMBL)
TRPC3/6/7ComplexR-HSA-426176 (Reactome)
TRPC6 ProteinQ9Y210 (Uniprot-TrEMBL)
TRPC7 ProteinQ9HCX4 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
1,2-daG3PArrowR-HSA-426240 (Reactome)
2AGArrowR-HSA-426032 (Reactome)
2AGR-HSA-426043 (Reactome)
3AGR-HSA-5694462 (Reactome)
AAArrowR-HSA-426043 (Reactome)
AAArrowR-HSA-5694462 (Reactome)
ABHD6,12mim-catalysisR-HSA-5694462 (Reactome)
ADPArrowR-HSA-426240 (Reactome)
ATPR-HSA-426240 (Reactome)
Ca2+ArrowR-HSA-139854 (Reactome)
Ca2+R-HSA-139854 (Reactome)
Ca2+R-HSA-392831 (Reactome)
CalDAG-GEFs:DAG:Ca2+ArrowR-HSA-392831 (Reactome)
CalDAG-GEFsR-HSA-392831 (Reactome)
DAG-activated TRPC3/6/7ArrowR-HSA-426209 (Reactome)
DAGR-HSA-392831 (Reactome)
DAGR-HSA-425861 (Reactome)
DAGR-HSA-426032 (Reactome)
DAGR-HSA-426209 (Reactome)
DAGR-HSA-426240 (Reactome)
Diacylglycerol kinasemim-catalysisR-HSA-426240 (Reactome)
Diacylglycerol lipasemim-catalysisR-HSA-426032 (Reactome)
Fatty AcidArrowR-HSA-426032 (Reactome)
GlycerolArrowR-HSA-426043 (Reactome)
GlycerolArrowR-HSA-5694462 (Reactome)
H+ArrowR-HSA-426043 (Reactome)
H+ArrowR-HSA-5694462 (Reactome)
H2OR-HSA-426043 (Reactome)
H2OR-HSA-5694462 (Reactome)
I(1,4,5)P3R-HSA-139941 (Reactome)
IP3R tetramer:I(1,4,5)P3:4xCa2+ArrowR-HSA-139941 (Reactome)
IP3R tetramer:I(1,4,5)P3:4xCa2+mim-catalysisR-HSA-139854 (Reactome)
IP3R tetramerR-HSA-139941 (Reactome)
MGLLmim-catalysisR-HSA-426043 (Reactome)
Protein kinase C, novel isoforms:DAGArrowR-HSA-425861 (Reactome)
Protein kinase C, novel isoformsR-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).
TRPC3/6/7R-HSA-426209 (Reactome)
Personal tools
Navigation