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 [ Rusten et al], annotated with biochemical interaction database [ Rhea], and diseases (depicted in pink) with corresponding [ OMIM-identifiers.]. Dashed lines depict proposed interactions which have not been characterized (yet).


Denise Slenter , Egon Willighagen , Elisa Santarsiero , and Eric Weitz


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Homo sapiens


Inherited Metabolic Disorders (IMD) Pathways Lipids and LIPID MAPS Rare Diseases


Disease Ontology

Charcot-Marie-Tooth disease type 4B1 centronuclear myopathy Fleck corneal dystrophy oculocerebrorenal syndrome

Pathway Ontology

phosphatidylinositol metabolic pathway


Label Type Compact URI Comment
PtdIns(5)P Metabolite chebi:57795 aka phosphatidylinositol 5-phosphate
phosphorylated on position 1 and 5; position 1 connected to DAG.
Localization: Nucleus
Function: 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-bisphosphate
Localization: Plasma membrane, Nucleus
Function: Endocytosis, cytoskeletal dynamics
PtdIns(3,5)P2 Metabolite chebi:57923 phosphorylated on position 1, 3 and 5; position 1 connected to DAG.
Localization: Endosomes
Function: 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: Endosomes
Function: 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 membrane
Function: Signaling, phagocyte oxidase, cytoskeletal dynamics
PtdIns(4)P Metabolite chebi:58178 phosphorylated on position 1 and 4; position 1 connected to DAG.
Localization: Golgi
Function: 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 membrane
Function: 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:
PIP-5 kinase alpha Protein uniprot:Q99755
4-phosphatase Protein eccode: From [ and] :'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.
PIP-4 kinase Protein eccode: 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
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:
PIP4P1 Protein uniprot:Q86T03
SHIP (1) Protein uniprot:Q92835 EC: Annotated based on caption of Fig. 1 [PMID:16554828] and 'Src homology 2 (SH2) domain containing inositol polyphosphate 5-phosphatase 1 (SHIP1)' []
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' []
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:
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
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
PI-3 kinase II Protein eccode: See also
PI3K-C2β Protein uniprot:O00750
PI3K-C2γ Protein uniprot:O75747
PIK3C3 Protein uniprot:Q8NEB9
PIK3R4 Protein uniprot:Q99570


  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. Analyzing phosphoinositides and their interacting proteins. Rusten TE, Stenmark H. Nat Methods. 2006 Apr;3(4):251–8. PubMed Europe PMC Scholia
  8. 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
  9. 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