Phosphoinositides metabolism (WP4971)
Homo sapiens
Phosphatidylinositols are a family of lipids under the phosphatidylglyceride class. This pathway specifies several metabolic conversions between PIP, PIP2, PIP3 and other metabolites. Phosphorylation sites on the individual metabolites are drawn as states, with the location added as a number. The main interactions within this pathway are based on Figure 1 of [https://doi.org/10.1038/nmeth867 Rusten et al], annotated with biochemical interaction database [https://www.rhea-db.org/ Rhea], and diseases (depicted in pink) with corresponding [https://www.omim.org/ OMIM-identifiers.]. Dashed lines depict proposed interactions which have not been characterised (yet)
Authors
Denise Slenter , Egon Willighagen , and Elisa SantarsieroActivity
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Organisms
Homo sapiensCommunities
Inherited Metabolic Disorders (IMD) Pathways Lipids and LIPID MAPS Rare DiseasesAnnotations
Disease Ontology
oculocerebrorenal syndrome Charcot-Marie-Tooth disease type 4B1 Fleck corneal dystrophy centronuclear myopathyPathway Ontology
phosphatidylinositol metabolic pathway| Label | Type | Compact URI | Comment |
|---|---|---|---|
| PtdIns(5)P | Metabolite | chebi:57795 | aka phosphatidylinositol 5-phosphatephosphorylated on position 1 and 5; position 1 connected to DAG.Localization: NucleusFunction: Apoptosis |
| DAG | Metabolite | chebi:17815 | Diacylglycerol |
| ATP | Metabolite | chebi:30616 | |
| H2O | Metabolite | chebi:15377 | |
| Phosphate | Metabolite | chebi:43474 | |
| PtdIns(4,5)P2 | Metabolite | chebi:58456 | phosphatidylinositol 4,5-bisphosphateLocalization: Plasma membrane, NucleusFunction: Endocytosis, cytoskeletal dynamics |
| PtdIns(3,5)P2 | Metabolite | chebi:57923 | phosphorylated on position 1, 3 and 5; position 1 connected to DAG.Localization: EndosomesFunction: Osmotic stress responses, signaling, vacuole homeostasis |
| PtdIns | Metabolite | chebi:57880 | phosphorylated on position 1; position 1 connected to DAG. |
| PtdIns(3)P | Metabolite | chebi:58088 | phosphorylated on position 1 and 3; position 1 connected to DAG.Localization: EndosomesFunction: Endocytic membrane traffic, autophagy, phagosome maturation |
| PtdIns(3,4)P2 | Metabolite | chebi:57658 | phosphorylated on position 1, 3 and 4; position 1 connected to DAG.Localization: Plasma membraneFunction: Signaling, phagocyte oxidase, cytoskeletal dynamics |
| PtdIns(4)P | Metabolite | chebi:58178 | phosphorylated on position 1 and 4; position 1 connected to DAG.Localization: GolgiFunction: Golgi-to-PM traffic |
| PtdIns(3,4,5)P3 | Metabolite | chebi:57836 | phosphorylated on position 1, 3, 4 and 5; position 1 connected to DAG.Localization: Plasma membraneFunction: Signaling, cytoskeletal dynamics |
| Ins(1,4,5)P3 | Metabolite | chebi:203600 | phosphorylated on position 1,4 and 5. |
| ADP | Metabolite | chebi:456216 | |
| H+ | Metabolite | chebi:15378 | |
| PI-3 kinase III | Protein | eccode:2.7.1.137 | |
| PIP-5 kinase alpha | Protein | uniprot:Q99755 | |
| 4-phosphatase | Protein | eccode:3.1.3.78 | From [https://www.qmul.ac.uk/sbcs/iubmb/enzyme/EC3/1/3/78.html and https://enzyme.expasy.org/EC/3.1.3.78] :'Two pathways exist in mammalian cells to degrade 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [PtdIns(4,5)P2] [2]. One is catalysed by this enzyme... The enzyme from human is specific for PtdIns(4,5)P2 as substrate, as it cannot use PtdIns(3,4,5)P3, PtdIns(3,4)P2, PtdIns(3,5)P2, PtdIns5P, PtdIns4P or PtdIns3P [2].In humans, the enzyme is localized to late endosomal/lysosomal membranes [2].' [2]: [PMID: 16365287] |
| PTEN | Protein | uniprot:P60484 | |
| SACM1L | Protein | uniprot:Q9NTJ5 | Annotation based on Uniprot ' Can also catalyze the hydrolysis of phosphatidylinositol 3-phosphate (PtdIns3P)' and EC.3.1.3.64 |
| PIP-4 kinase | Protein | eccode:2.7.1.149 | According to Rhea, this is the EC class. |
| PLCB2 | Protein | uniprot:Q00722 | |
| MTMR1 | Protein | uniprot:Q13613 | |
| PIKfyve | Protein | uniprot:Q9Y2I7 | |
| PLCH1 | Protein | uniprot:Q4KWH8 | |
| PI3K-C2α | Protein | uniprot:O00443 | |
| PTEN | Protein | uniprot:P60484 | |
| PLCG1 | Protein | uniprot:P19174 | |
| MTM1 | Protein | uniprot:Q13496 | aka Myotubularin; gene name given in Fig. 1 of [PMID:16554828]. |
| OCRL | Protein | uniprot:Q01968 | |
| PLCB1 | Protein | uniprot:Q9NQ66 | |
| PIK3CG | Protein | uniprot:P48736 | |
| PI-3 kinase I | Protein | eccode:2.7.1.137 | |
| PIP4P1 | Protein | uniprot:Q86T03 | |
| SHIP (1) | Protein | uniprot:Q92835 | EC:3.1.3.86. Annotated based on caption of Fig. 1 [PMID:16554828] and 'Src homology 2 (SH2) domain containing inositol polyphosphate 5-phosphatase 1 (SHIP1)' [https://en.wikipedia.org/wiki/INPP5D] |
| PIP-5 kinase gamma | Protein | uniprot:O60331 | 'PIP5Kγ, has three splicing variance; PIP5Kγ635, PIP5γ661, and PIP5Kγ687, making it one of the key regulators for producing PI(4,5)P2' [https://en.wikipedia.org/wiki/Phosphatidylinositol-4-phosphate_5-_kinases_(PIP5K)_in_neuronal_development] |
| PIP4K2A | Protein | uniprot:P48426 | |
| PIP4K2C | Protein | uniprot:Q8TBX8 | |
| PIP4K2B | Protein | uniprot:P78356 | |
| PIP4P2 | Protein | uniprot:Q8N4L2 | |
| PIP-5 kinase beta | Protein | uniprot:O14986 | |
| PIK3CB | Protein | uniprot:P42338 | |
| PIK3CA | Protein | uniprot:P42336 | |
| PIK3CD | Protein | uniprot:O00329 | |
| Phospholipase C | Protein | eccode:3.1.4.11 | |
| PLCB3 | Protein | uniprot:Q01970 | |
| PLCB4 | Protein | uniprot:Q15147 | |
| PLCG2 | Protein | uniprot:P16885 | |
| PLCE1 | Protein | uniprot:Q9P212 | |
| PLCD1 | Protein | uniprot:P51178 | |
| PLCD3 | Protein | uniprot:Q8N3E9 | |
| PLCD4 | Protein | uniprot:Q9BRC7 | |
| PLCH2 | Protein | uniprot:O75038 | |
| PLCZ1 | Protein | uniprot:Q86YW0 | |
| PIK3CG | Protein | uniprot:P48736 | |
| PI-3 kinase I | Protein | eccode:2.7.1.137 | |
| PIK3CB | Protein | uniprot:P42338 | |
| PIK3CA | Protein | uniprot:P42336 | |
| PIK3CD | Protein | uniprot:O00329 | |
| PIP-5 kinase alpha | Protein | uniprot:Q99755 | |
| PIP-5 kinase gamma | Protein | uniprot:O60331 | 'PIP5Kγ, has three splicing variance; PIP5Kγ635, PIP5γ661, and PIP5Kγ687, making it one of the key regulators for producing PI(4,5)P2' [https://en.wikipedia.org/wiki/Phosphatidylinositol-4-phosphate_5-_kinases_(PIP5K)_in_neuronal_development] |
| PIP-5 kinase beta | Protein | uniprot:O14986 | |
| 4-phosphatase | Protein | eccode:3.1.3.78 | From [https://www.qmul.ac.uk/sbcs/iubmb/enzyme/EC3/1/3/78.html and https://enzyme.expasy.org/EC/3.1.3.78] :'Two pathways exist in mammalian cells to degrade 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [PtdIns(4,5)P2] [2]. One is catalysed by this enzyme... The enzyme from human is specific for PtdIns(4,5)P2 as substrate, as it cannot use PtdIns(3,4,5)P3, PtdIns(3,4)P2, PtdIns(3,5)P2, PtdIns5P, PtdIns4P or PtdIns3P [2].In humans, the enzyme is localized to late endosomal/lysosomal membranes [2].' [2]: [PMID: 16365287] |
| PIP4P1 | Protein | uniprot:Q86T03 | |
| PIP4P2 | Protein | uniprot:Q8N4L2 | |
| PIP-4 kinase | Protein | eccode:2.7.1.149 | According to Rhea, this is the EC class. |
| PIP4K2A | Protein | uniprot:P48426 | |
| PIP4K2C | Protein | uniprot:Q8TBX8 | |
| PIP4K2B | Protein | uniprot:P78356 | |
| MTMR10 | Protein | uniprot:Q9NXD2 | |
| MTMR11 | Protein | uniprot:A4FU01 | |
| MTMR12 | Protein | uniprot:Q9C0I1 | |
| MTMR2 | Protein | uniprot:Q13614 | |
| MTMR3 | Protein | uniprot:Q13615 | |
| MTMR4 | Protein | uniprot:Q9NYA4 | |
| MTMR6 | Protein | uniprot:Q9Y217 | |
| MTMR7 | Protein | uniprot:Q9Y216 | |
| MTMR8 | Protein | uniprot:Q96EF0 | |
| MTMR9 | Protein | uniprot:Q96QG7 | |
| SBF2 | Protein | uniprot:Q86WG5 | aka Myotubularin-related protein 13 |
| SBF1 | Protein | uniprot:O95248 | aka Myotubularin-related protein 5 |
| PIK3CG | Protein | uniprot:P48736 | |
| PI-3 kinase I | Protein | eccode:2.7.1.137 | |
| PIK3CB | Protein | uniprot:P42338 | |
| PIK3CA | Protein | uniprot:P42336 | |
| PIK3CD | Protein | uniprot:O00329 | |
| PI-3 kinase II | Protein | eccode:2.7.1.154 | See also https://en.wikipedia.org/wiki/Class_II_PI_3-kinases |
| PI3K-C2β | Protein | uniprot:O00750 | |
| PI3K-C2γ | Protein | uniprot:O75747 | |
| PIK3C3 | Protein | uniprot:Q8NEB9 | |
| PIK3R4 | Protein | uniprot:Q99570 | |
| MTM1 | Protein | uniprot:Q13496 | aka Myotubularin; gene name given in Fig. 1 of [PMID:16554828]. |
References
- A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Laporte J, Hu LJ, Kretz C, Mandel JL, Kioschis P, Coy JF, et al. Nat Genet. 1996 Jun;13(2):175–82. PubMed Europe PMC Scholia
- A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate. Rameh LE, Tolias KF, Duckworth BC, Cantley LC. Nature. 1997 Nov 13;390(6656):192–6. PubMed Europe PMC Scholia
- Structure, function, and biology of SHIP proteins. Rohrschneider LR, Fuller JF, Wolf I, Liu Y, Lucas DM. Genes Dev. 2000 Mar 1;14(5):505–20. PubMed Europe PMC Scholia
- Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Bolino A, Muglia M, Conforti FL, LeGuern E, Salih MA, Georgiou DM, et al. Nat Genet. 2000 May;25(1):17–9. PubMed Europe PMC Scholia
- Mutations in PIP5K3 are associated with François-Neetens mouchetée fleck corneal dystrophy. Li S, Tiab L, Jiao X, Munier FL, Zografos L, Frueh BE, et al. Am J Hum Genet. 2005 Jul;77(1):54–63. PubMed Europe PMC Scholia
- The identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases. Ungewickell A, Hugge C, Kisseleva M, Chang SC, Zou J, Feng Y, et al. Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):18854–9. PubMed Europe PMC Scholia
- Analyzing phosphoinositides and their interacting proteins. Rusten TE, Stenmark H. Nat Methods. 2006 Apr;3(4):251–8. PubMed Europe PMC Scholia
- The regulation and function of Class III PI3Ks: novel roles for Vps34. Backer JM. Biochem J. 2008 Feb 15;410(1):1–17. PubMed Europe PMC Scholia
- PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K. Malek M, Kielkowska A, Chessa T, Anderson KE, Barneda D, Pir P, et al. Mol Cell. 2017 Nov 2;68(3):566-580.e10. PubMed Europe PMC Scholia