PathwayStep1824 PathwayStep1826 PathwayStep1803 PathwayStep1805 PathwayStep1848 PathwayStep1846 PathwayStep1835 PathwayStep1837 PathwayStep1839 PathwayStep1791 PathwayStep1717 PI and PC transport between ER and Golgi membranes PIPs transport between Golgi and plasma membranes Synthesis of PIPs at the Golgi membrane PI Metabolism Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0006644 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.<br><br>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.<br><br>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). Pubmed15170460 Pubmed15269334 Pubmed16828287 Pubmed17035995 Pubmed17330069 Pubmed17605038 Pubmed18216767 Pubmed18216768 Pubmed18726176 Pubmed18784754 Pubmed19196647 Pubmed20043944 Pubmed20192774 Pubmed20559318 Pubmed20861159 Reactome Database ID Release 431483255 Reactome, http://www.reactome.org ReactomeREACT_121175 Reviewed: Wakelam, Michael, 2012-05-14 Synthesis of PIPs at the ER membrane PIPs transport between late endosome and Golgi membranes PIPs transport between early and late endosome membranes Synthesis of PIPs at the late endosome membrane Synthesis of PIPs at the early endosome membrane PIPs transport between early endosome and Golgi membranes Synthesis of PIPs at the plasma membrane PIPs transport between plasma and early endosome membranes