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MetaCyc Pathway: 3-phosphoinositide degradation
Inferred by curatorInferred from experiment

Pathway diagram: 3-phosphoinositide degradation

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: phosphatidyl-inositol 3,4,5-trisphosphate degradation

Superclasses: Degradation/Utilization/AssimilationFatty Acid and Lipids Degradation

Some taxa known to possess this pathway include : Homo sapiens, Saccharomyces cerevisiae

Expected Taxonomic Range: Eukaryota

Phosphoinositides play a key role in signal transduction in the eukaryotic cell, transmitting signals from the cell surface to modulate intracellular processes. The 3-phosphoinositides, which contain the monophosphate phosphatidylinositol 3-phosphate, the bisphosphate phosphatidylinositol 3,4-bisphosphate and the trisphosphate phosphatidylinositol 3,4,5-trisphosphate, are particularly important in signaling cascades that influence a wide variety of cellular functions. These compounds are.generated by the action of several phosphatidylinositol 3-kinases (PI 3-kinases), as described in the pathway 3-phosphoinositide biosynthesis.

The levels of specific phosphoinositide pools are regulated by intricate networks of enzymes and proteins that govern the rates of phosphoinositide synthesis, transport, and degradation.

Phosphatidylinositol 3,4,5-trisphosphate is a transient plasma membrane signal, and is rapidly hydrolyzed by a 5-phosphatase reaction to phosphatidylinositol 3,4-bisphosphate or by a 3-phosphatase reaction to phosphatidylinositol 4,5-bisphosphate.

The 5-phosphatase reaction is catalyzed by several inositol polyphosphate 5-phosphatases that belong to groups type II ( INPP5B, SYNJ1, SYNJ2, OCRL, INPP5K, INPP5F), type III ( INPPL1, INPP5D) and type IV ( INPP5E).

The 3-phosphatase reaction is catayzed by phosphatidylinositol-3,4,5-trisphosphate 3-phosphatas PTEN [Stephens93, Mitchell02]. The importance of this reaction is made clear by the fact that mutations in this gene are found in a high percentage of human tumors, and particularly in glioblastoma, melanoma, and prostate and endometrial carcinomas [GinnPease03, Kurose02, Kanamori02, Frisk02, Mercapide02, Eng02, Staal02].

The bisphosphate products can also be degraded. Phosphatidylinositol 3,4-bisphosphate, an important second messenger on its own, is considered a more sustained signal, and lasts for up to 60 min before being hydrolyzed to form a 1-phosphatidyl-1D-myo-inositol 3-phosphate by the inositol polyphosphate 4-phosphatases ( INPP4A and INPP4B) [Banfic98, Marshall02]. It can also be hydrolyzed by PTEN to form a 1-phosphatidyl-1D-myo-inositol 4-phosphate.

phosphatidylinositol 4,5-bisphosphate, is hydrolyzed by either 4-phosphatases ( TMEM55A and TMEM55B) or the same 5-phosphatases listed above, resulting in a 1-phosphatidyl-1D-myo-inositol 5-phosphate or a 1-phosphatidyl-1D-myo-inositol 4-phosphate, respectively.

Finally, each of the monophosphates has been shown to be degraded by a specific enzyme, resulting in the formation of an L-1-phosphatidyl-inositol, which is recycled back to the membrane.

Created 26-Oct-2009 by Caspi R, SRI International


Banfic98: Banfic H, Tang X, Batty IH, Downes CP, Chen C, Rittenhouse SE (1998). "A novel integrin-activated pathway forms PKB/Akt-stimulatory phosphatidylinositol 3,4-bisphosphate via phosphatidylinositol 3-phosphate in platelets." J Biol Chem 273(1);13-6. PMID: 9417038

Carricaburu03: Carricaburu V, Lamia KA, Lo E, Favereaux L, Payrastre B, Cantley LC, Rameh LE (2003). "The phosphatidylinositol (PI)-5-phosphate 4-kinase type II enzyme controls insulin signaling by regulating PI-3,4,5-trisphosphate degradation." Proc Natl Acad Sci U S A 100(17);9867-72. PMID: 12897244

Clarke01: Clarke JH, Letcher AJ, D'santos CS, Halstead JR, Irvine RF, Divecha N (2001). "Inositol lipids are regulated during cell cycle progression in the nuclei of murine erythroleukaemia cells." Biochem J 357(Pt 3);905-10. PMID: 11463365

Eng02: Eng C (2002). "Role of PTEN, a lipid phosphatase upstream effector of protein kinase B, in epithelial thyroid carcinogenesis." Ann N Y Acad Sci 968;213-21. PMID: 12119278

Frisk02: Frisk T, Foukakis T, Dwight T, Lundberg J, Hoog A, Wallin G, Eng C, Zedenius J, Larsson C (2002). "Silencing of the PTEN tumor-suppressor gene in anaplastic thyroid cancer." Genes Chromosomes Cancer 35(1);74-80. PMID: 12203792

GinnPease03: Ginn-Pease ME, Eng C (2003). "Increased nuclear phosphatase and tensin homologue deleted on chromosome 10 is associated with G0-G1 in MCF-7 cells." Cancer Res 63(2);282-6. PMID: 12543774

Gozani03: Gozani O, Karuman P, Jones DR, Ivanov D, Cha J, Lugovskoy AA, Baird CL, Zhu H, Field SJ, Lessnick SL, Villasenor J, Mehrotra B, Chen J, Rao VR, Brugge JS, Ferguson CG, Payrastre B, Myszka DG, Cantley LC, Wagner G, Divecha N, Prestwich GD, Yuan J (2003). "The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor." Cell 114(1);99-111. PMID: 12859901

Ivetac05: Ivetac I, Munday AD, Kisseleva MV, Zhang XM, Luff S, Tiganis T, Whisstock JC, Rowe T, Majerus PW, Mitchell CA (2005). "The type Ialpha inositol polyphosphate 4-phosphatase generates and terminates phosphoinositide 3-kinase signals on endosomes and the plasma membrane." Mol Biol Cell 16(5);2218-33. PMID: 15716355

Kanamori02: Kanamori Y, Kigawa J, Itamochi H, Sultana H, Suzuki M, Ohwada M, Kamura T, Sugiyama T, Kikuchi Y, Kita T, Fujiwara K, Terakawa N (2002). "PTEN expression is associated with prognosis for patients with advanced endometrial carcinoma undergoing postoperative chemotherapy." Int J Cancer 100(6);686-9. PMID: 12209607

Kurose02: Kurose K, Gilley K, Matsumoto S, Watson PH, Zhou XP, Eng C (2002). "Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas." Nat Genet 32(3);355-7. PMID: 12379854

Lecompte08: Lecompte O, Poch O, Laporte J (2008). "PtdIns5P regulation through evolution: roles in membrane trafficking?." Trends Biochem Sci 33(10);453-60. PMID: 18774718

Marshall02: Marshall AJ, Krahn AK, Ma K, Duronio V, Hou S (2002). "TAPP1 and TAPP2 are targets of phosphatidylinositol 3-kinase signaling in B cells: sustained plasma membrane recruitment triggered by the B-cell antigen receptor." Mol Cell Biol 22(15);5479-91. PMID: 12101241

Meijer01: Meijer HJ, Berrie CP, Iurisci C, Divecha N, Musgrave A, Munnik T (2001). "Identification of a new polyphosphoinositide in plants, phosphatidylinositol 5-monophosphate (PtdIns5P), and its accumulation upon osmotic stress." Biochem J 360(Pt 2);491-8. PMID: 11716778

Mercapide02: Mercapide J, Zhang SY, Fan X, Furio-Bacete V, Schneider J, Lopez de la Osa I, Patchefsky AS, Klein-Szanto AJ, Castresana JS (2002). "CCND1- and ERBB2-gene deregulation and PTEN mutation analyses in invasive lobular carcinoma of the breast." Mol Carcinog 35(1);6-12. PMID: 12203362

Mitchell02: Mitchell CA, Gurung R, Kong AM, Dyson JM, Tan A, Ooms LM (2002). "Inositol polyphosphate 5-phosphatases: lipid phosphatases with flair." IUBMB Life 53(1);25-36. PMID: 12018404

Morris00: Morris JB, Hinchliffe KA, Ciruela A, Letcher AJ, Irvine RF (2000). "Thrombin stimulation of platelets causes an increase in phosphatidylinositol 5-phosphate revealed by mass assay." FEBS Lett 475(1);57-60. PMID: 10854858

Pagliarini04: Pagliarini DJ, Worby CA, Dixon JE (2004). "A PTEN-like phosphatase with a novel substrate specificity." J Biol Chem 279(37);38590-6. PMID: 15247229

Rohde02: Rohde G, Wenzel D, Haucke V (2002). "A phosphatidylinositol (4,5)-bisphosphate binding site within mu2-adaptin regulates clathrin-mediated endocytosis." J Cell Biol 158(2);209-14. PMID: 12119359

Schaletzky03: Schaletzky J, Dove SK, Short B, Lorenzo O, Clague MJ, Barr FA (2003). "Phosphatidylinositol-5-phosphate activation and conserved substrate specificity of the myotubularin phosphatidylinositol 3-phosphatases." Curr Biol 13(6);504-9. PMID: 12646134

Shearn01: Shearn CT, Walker J, Norris FA (2001). "Identification of a novel spliceoform of inositol polyphosphate 4-phosphatase type Ialpha expressed in human platelets: structure of human inositol polyphosphate 4-phosphatase type I gene." Biochem Biophys Res Commun 286(1);119-25. PMID: 11485317

Staal02: Staal FJ, van der Luijt RB, Baert MR, van Drunen J, van Bakel H, Peters E, de Valk I, van Amstel HK, Taphoorn MJ, Jansen GH, van Veelen CW, Burgering B, Staal GE (2002). "A novel germline mutation of PTEN associated with brain tumours of multiple lineages." Br J Cancer 86(10);1586-91. PMID: 12085208

Stephens93: Stephens LR, Jackson TR, Hawkins PT (1993). "Agonist-stimulated synthesis of phosphatidylinositol(3,4,5)-trisphosphate: a new intracellular signalling system?." Biochim Biophys Acta 1179(1);27-75. PMID: 8399352

Zhang98f: Zhang X, Majerus PW (1998). "Phosphatidylinositol signalling reactions." Semin Cell Dev Biol 9(2);153-60. PMID: 9599410

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Attree92: Attree O, Olivos IM, Okabe I, Bailey LC, Nelson DL, Lewis RA, McInnes RR, Nussbaum RL (1992). "The Lowe's oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase." Nature 358(6383);239-42. PMID: 1321346

Bansal90: Bansal VS, Caldwell KK, Majerus PW (1990). "The isolation and characterization of inositol polyphosphate 4-phosphatase." J Biol Chem 265(3);1806-11. PMID: 2153145

Chi09: Chi A, Rhee S (2009). "The functional annotation of Arabidopsis protein sequences was performed by BLAST queries against a reference set of experimentally verified enzymes. For each Arabidopsis sequence, the enzymatic activity of the top BLAST hit (or hits if they had equivalent E-values) was assigned to the protein if its E-value fell below a specific E-value threshold established for the corresponding enzymatic activity. Note: The annotation thresholds were established by doing a self BLAST of the reference enzyme dataset. For each enzymatic activity represented by multiple proteins, the mean E-value of all the correct hits generated by the self BLAST was selected as the cut-off. All of these means were averaged and used as the cut-off for assigning annotations for any enzymatic activities that were represented by a single protein in the reference dataset."

Cleves89: Cleves AE, Novick PJ, Bankaitis VA (1989). "Mutations in the SAC1 gene suppress defects in yeast Golgi and yeast actin function." J Cell Biol 109(6 Pt 1);2939-50. PMID: 2687291

Cremona00: Cremona O, Nimmakayalu M, Haffner C, Bray-Ward P, Ward DC, De Camilli P (2000). "Assignment of SYNJ1 to human chromosome 21q22.2 and Synj12 to the murine homologous region on chromosome 16C3-4 by in situ hybridization." Cytogenet Cell Genet 88(1-2);89-90. PMID: 10773674

Damen96: Damen JE, Liu L, Rosten P, Humphries RK, Jefferson AB, Majerus PW, Krystal G (1996). "The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase." Proc Natl Acad Sci U S A 93(4);1689-93. PMID: 8643691

Drayer96: Drayer AL, Pesesse X, De Smedt F, Woscholski R, Parker P, Erneux C (1996). "Cloning and expression of a human placenta inositol 1,3,4,5-tetrakisphosphate and phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase." Biochem Biophys Res Commun 225(1);243-9. PMID: 8769125

Ercetin04: Ercetin ME, Gillaspy GE (2004). "Molecular characterization of an Arabidopsis gene encoding a phospholipid-specific inositol polyphosphate 5-phosphatase." Plant Physiol 135(2);938-46. PMID: 15181205

Erneux98: Erneux C, Govaerts C, Communi D, Pesesse X (1998). "The diversity and possible functions of the inositol polyphosphate 5-phosphatases." Biochim Biophys Acta 1436(1-2);185-99. PMID: 9838104

Foti01: Foti M, Audhya A, Emr SD (2001). "Sac1 lipid phosphatase and Stt4 phosphatidylinositol 4-kinase regulate a pool of phosphatidylinositol 4-phosphate that functions in the control of the actin cytoskeleton and vacuole morphology." Mol Biol Cell 12(8);2396-411. PMID: 11514624

Galandrini02: Galandrini R, Tassi I, Mattia G, Lenti L, Piccoli M, Frati L, Santoni A (2002). "SH2-containing inositol phosphatase (SHIP-1) transiently translocates to raft domains and modulates CD16-mediated cytotoxicity in human NK cells." Blood 100(13);4581-9. PMID: 12393695

Guo99: Guo S, Stolz LE, Lemrow SM, York JD (1999). "SAC1-like domains of yeast SAC1, INP52, and INP53 and of human synaptojanin encode polyphosphoinositide phosphatases." J Biol Chem 274(19);12990-5. PMID: 10224048

Habib98: Habib T, Hejna JA, Moses RE, Decker SJ (1998). "Growth factors and insulin stimulate tyrosine phosphorylation of the 51C/SHIP2 protein." J Biol Chem 273(29);18605-9. PMID: 9660833

Haffner97: Haffner C, Takei K, Chen H, Ringstad N, Hudson A, Butler MH, Salcini AE, Di Fiore PP, De Camilli P (1997). "Synaptojanin 1: localization on coated endocytic intermediates in nerve terminals and interaction of its 170 kDa isoform with Eps15." FEBS Lett 419(2-3);175-80. PMID: 9428629

Ijuin00: Ijuin T, Mochizuki Y, Fukami K, Funaki M, Asano T, Takenawa T (2000). "Identification and characterization of a novel inositol polyphosphate 5-phosphatase." J Biol Chem 275(15);10870-5. PMID: 10753883

Jackson95: Jackson SP, Schoenwaelder SM, Matzaris M, Brown S, Mitchell CA (1995). "Phosphatidylinositol 3,4,5-trisphosphate is a substrate for the 75 kDa inositol polyphosphate 5-phosphatase and a novel 5-phosphatase which forms a complex with the p85/p110 form of phosphoinositide 3-kinase." EMBO J 14(18);4490-500. PMID: 7556092

Jefferson95: Jefferson AB, Majerus PW (1995). "Properties of type II inositol polyphosphate 5-phosphatase." J Biol Chem 270(16);9370-7. PMID: 7721860

Jefferson97: Jefferson AB, Auethavekiat V, Pot DA, Williams LT, Majerus PW (1997). "Signaling inositol polyphosphate-5-phosphatase. Characterization of activity and effect of GRB2 association." J Biol Chem 272(9);5983-8. PMID: 9038219

Joseph99: Joseph RE, Walker J, Norris FA (1999). "Assignment of the inositol polyphosphate 4-phosphatase type I gene (INPP4A) to human chromosome band 2q11.2 by in situ hybridization." Cytogenet Cell Genet 87(3-4);276-7. PMID: 10702694

Kavanaugh96: Kavanaugh WM, Pot DA, Chin SM, Deuter-Reinhard M, Jefferson AB, Norris FA, Masiarz FR, Cousens LS, Majerus PW, Williams LT (1996). "Multiple forms of an inositol polyphosphate 5-phosphatase form signaling complexes with Shc and Grb2." Curr Biol 6(4);438-45. PMID: 8723348

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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