PI Metabolism

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Homo sapiens
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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
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