Reactome | PI Metabolism

PI Metabolism

Stable Identifier

R-HSA-1483255

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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Phosphatidylinositol (PI), a membrane phospholipid, can be reversibly phosphorylated at the 3, 4, and 5 positions of the inositol ring to generate seven phosphoinositides: phosphatidylinositol 3-phosphate (PI3P), phosphatidylinositol 4-phosphate (PI4P), phosphatidylinositol 5-phosphate (PI5P), phosphatidylinositol 3,4-bisphosphate PI(3,4)P2, phosphatidylinositol 4,5-bisphosphate PI(4,5)P2, phosphatidylinositol 3,5-bisphosphate PI(3,5)P2, and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3). These seven phosphoinositides, which are heterogeneously distributed within cells, can serve as signature components of different intracellular compartment membranes and so help to mediate specificity of membrane interactions. Phosphoinositide levels are tightly regulated spatially and temporally by the action of various kinases and phosphatases whilst PI(4,5)P2 is also a substrate for phospholipase C. The differential localisation of each of these enzymes on specific compartment membranes ensures maintenance of the heterogeneous distribution of phosphoinositides despite the continuous membrane flow from one compartment to another.

PI is primarily synthesised in the endoplasmic reticulum from where the phospholipid is exported to other compartments via membrane traffic or via cytosolic phospholipid transfer proteins. Phosphorylation of PI to PI4P primarily occurs in the Golgi, where PI4P plays an important role in the biogenesis of transport vesicles such as the secretory vesicle involved in its transport to the plasma membrane. At this place, PI4P has a major function acting as a precursor of PI(4,5)P2, which is located predominantly at this membrane. PI(4,5)P2 binds and regulates a wide range of proteins that function on the cell surface and serves as a precursor for second messengers. Additionally, it helps define this membrane as a target for secretory vesicles, functions as a coreceptor in endocytic processes, and functions as a cofactor for actin nucleation.

At the plasma membrane, PI(4,5)P2 is further phosphorylated to PI(3,4,5)P3, another phosphoinositide with important signalling functions including stimulating cell survival and proliferation. The inositol 3-phosphatase, phosphatase and tensin homolog (PTEN) regenerates PI(4,5)P2, while the 5-phosphatases convert PI(3,4,5)P3 into the phosphoinositide, PI(3,4)P2, propagating the signal initiated by PI(3,4,5)P3. PI(3,4)P2 is further dephosphorylated in the endocytic pathway by inositol 4-phosphatases to PI3P, the signature phosphoinositide of the early endosomal compartment and a ligand for numerous endosomal proteins. However, the bulk of PI3P is generated directly in the endosomes by phosphorylation of PI. The subsequent endosomal phosphorylation of PI3P to PI(3,5)P2 is believed to generate docking sites for recruitment of cytosolic factors responsible for the control of outgoing traffic from the endosomes. The main localisation and function of the low abundance phosphoinositide PI5P, that can be generated by several pathways, remains to be determined (Krauss & Haucke 2007, Leventis & Grinstein 2010, Roth 2004, Gees et al. 2010, De Matteis & Godi 2004, van Meer et al. 2008, Vicinanza et al. 2008, Lemmon 2008, Kutaleladze 2010, Robinson & Dixon 2006, Blero et al. 2007, Liu & Bankaitis 2010, McCrea & De Camilli 2009, Vicinanza et al. 2008, Di Paolo & De Camilli, 2006).

Literature References

PubMed ID	Title	Journal	Year
19196647	Mutations in phosphoinositide metabolizing enzymes and human disease McCrea, HJ, De Camilli, P	Physiology (Bethesda)	2009
20861159	The role of transient receptor potential cation channels in Ca2+ signaling Gees, M, Nilius, B, Colsoul, B	Cold Spring Harb Perspect Biol	2010
20192774	The distribution and function of phosphatidylserine in cellular membranes Leventis, PA, Grinstein, S	Annu Rev Biophys	2010
20043944	Phosphoinositide phosphatases in cell biology and disease Liu, Y, Bankaitis, VA	Prog Lipid Res	2010
20559318	Translation of the phosphoinositide code by PI effectors Kutateladze, TG	Nat Chem Biol	2010
17605038	Phosphoinositide phosphatases in a network of signalling reactions Payrastre, B, Blero, D, Schurmans, S, Erneux, C	Pflugers Arch	2007
16828287	Myotubularin phosphatases: policing 3-phosphoinositides Robinson, FL, Dixon, JE	Trends Cell Biol	2006
18216768	Membrane lipids: where they are and how they behave van Meer, G, Voelker, DR, Feigenson, GW	Nat Rev Mol Cell Biol	2008
18216767	Membrane recognition by phospholipid-binding domains Lemmon, MA	Nat Rev Mol Cell Biol	2008
18726176	Phosphoinositides as regulators of membrane trafficking in health and disease Vicinanza, M, Di Campli, A, De Matteis, MA, D'Angelo, G	Cell Mol Life Sci	2008
17035995	Phosphoinositides in cell regulation and membrane dynamics Di Paolo, G, De Camilli, P	Nature	2006
17330069	Phosphoinositide-metabolizing enzymes at the interface between membrane traffic and cell signalling Krauss, M, Haucke, V	EMBO Rep	2007
15269334	Phosphoinositides in constitutive membrane traffic Roth, MG	Physiol Rev	2004
18784754	Function and dysfunction of the PI system in membrane trafficking Vicinanza, M, Di Campli, A, De Matteis, MA, D'Angelo, G	EMBO J	2008
15170460	PI-loting membrane traffic Godi, A, De Matteis, MA	Nat Cell Biol	2004