Phosphatidylinositol (3,4,5)-trisphosphate(PtdIns(3,4,5)P3), abbreviatedPIP3,is the product of the class Iphosphoinositide 3-kinases' (PI 3-kinases) phosphorylation ofphosphatidylinositol (4,5)-bisphosphate(PIP2). It is aphospholipidthat resides on the plasma membrane.
| |
| Names | |
|---|---|
| Other names
PI(3,4,5)P3,PtdIns(3,4,5)P3
| |
| Identifiers | |
| ChEBI | |
| KEGG | |
| Properties | |
| C47H86O22P4 | |
| Molar mass | 1126.46 g/mol, neutral with fatty acid composition - 18:0, 20:4 |
Except where otherwise noted, data are given for materials in theirstandard state(at 25 °C [77 °F], 100 kPa).
| |
Discovery
editIn 1988,Lewis C. Cantleypublished a paper describing the discovery of a novel type of phosphoinositide kinase with the unprecedented ability to phosphorylate the 3' position of the inositol ring resulting in the formation of phosphatidylinositol-3-phosphate (PI3P).[1]Working independently, Alexis Traynor-Kaplan and coworkers published a paper demonstrating that a novel lipid, phosphatidylinositol 3,4,5 trisphosphate (PIP3) occurs naturally in humanneutrophilswith levels that increased rapidly following physiologic stimulation with chemotactic peptide.[2]Subsequent studies demonstrated thatin vivothe enzyme originally identified by Cantley's group prefers PtdIns(4,5)P2 as a substrate, producing the product PIP3.[3]
Function
editPIP3functions to activate downstream signaling components, the most notable one being the protein kinaseAkt,which activates downstream anabolic signaling pathways required for cell growth and survival.[4]
PtdIns(3,4,5)P3is dephosphorylated by thephosphatasePTENon the 3 position, generatingPI(4,5)P2,and by SHIPs (SH2-containing inositol phosphatase) on the 5' position of theinositolring, producingPI(3,4)P2.[5]
ThePH domainin a number of proteins binds to PtdIns(3,4,5)P3.Such proteins includeAkt/PKB,[6]PDPK1,[7]Btk1, andARNO.[8]
Roles in the nervous system
editPIP3 plays a critical role outside the cytosol, notably at the postsynaptic terminal of hippocampal cells. Here, PIP3 has been implicated in regulating synaptic strengthening andAMPA expression,contributing tolong-term potentiation.Moreover, PIP3 suppression disrupts normal AMPA expression on the neuron membrane and instead leads to the accumulation of AMPA on dendritic spines, commonly associated withsynaptic depression.[9]
PIP3 interacts with proteins to mediatesynaptic plasticity.Of these proteins,Phldb2has been shown to interact with PIP3 to induce and maintain long-term potentiation. In the absence of such an interaction, memory consolidation is impaired.[10]
References
edit- ^Whitman M, Downes CP, Keeler M, Keller T, Cantley L (April 1988). "Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate".Nature.332(6165): 644–6.Bibcode:1988Natur.332..644W.doi:10.1038/332644a0.PMID2833705.S2CID4326568.
- ^Traynor-Kaplan AE, Harris AL, Thompson BL, Taylor P, Sklar LA (July 1988). "An inositol tetrakisphosphate-containing phospholipid in activated neutrophils".Nature.334(6180): 353–6.Bibcode:1988Natur.334..353T.doi:10.1038/334353a0.PMID3393226.S2CID4263472.
- ^Auger KR, Serunian LA, Soltoff SP, Libby P, Cantley LC (April 1989). "PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells".Cell.57(1): 167–75.doi:10.1016/0092-8674(89)90182-7.PMID2467744.S2CID22154860.
- ^Ma, Qi; Zhu, Chongzhuo; Zhang, Weilin; Ta, Na; Zhang, Rong; Liu, Lei; Feng, Du; Cheng, Heping; Liu, Junling; Chen, Quan (January 2019)."Mitochondrial PIP3-binding protein FUNDC2 supports platelet survival via AKT signaling pathway".Cell Death and Differentiation.26(2): 321–331.doi:10.1038/s41418-018-0121-8.ISSN1476-5403.PMC6329745.PMID29786068.
- ^Qi, Yanmei; Liu, Jie; Chao, Joshua; Greer, Peter A.; Li, Shaohua (2020-09-07)."PTEN dephosphorylates Abi1 to promote epithelial morphogenesis".The Journal of Cell Biology.219(9).doi:10.1083/jcb.201910041.ISSN1540-8140.PMC7480098.PMID32673396.
- ^Eramo, Matthew J.; Mitchell, Christina A. (February 2016)."Regulation of PtdIns(3,4,5)P3/Akt signalling by inositol polyphosphate 5-phosphatases"(PDF).Biochemical Society Transactions.44(1): 240–252.doi:10.1042/BST20150214.ISSN1470-8752.PMID26862211.
- ^Gagliardi, Paolo Armando; Puliafito, Alberto; Primo, Luca (February 2018)."PDK1: At the crossroad of cancer signaling pathways".Seminars in Cancer Biology.48:27–35.doi:10.1016/j.semcancer.2017.04.014.ISSN1096-3650.PMID28473254.
- ^Venkateswarlu, Kanamarlapudi; Oatey, Paru B.; Tavaré, Jeremy M.; Cullen, Peter J. (April 1998)."Insulin-dependent translocation of ARNO to the plasma membrane of adipocytes requires phosphatidylinositol 3-kinase".Current Biology.8(8): 463–466.Bibcode:1998CBio....8..463V.doi:10.1016/s0960-9822(98)70181-2.ISSN0960-9822.PMID9550703.S2CID12974067.
- ^Arendt, Kristin L.; Royo, María; Fernández-Monreal, Mónica; Knafo, Shira; Petrok, Cortney N.; Martens, Jeffrey R.; Esteban, José A. (January 2010)."PIP3 controls synaptic function by maintaining AMPA receptor clustering at the postsynaptic membrane".Nature Neuroscience.13(1): 36–44.doi:10.1038/nn.2462.ISSN1546-1726.PMC2810846.PMID20010819.
- ^Xie, Min-Jue; Ishikawa, Yasuyuki; Yagi, Hideshi; Iguchi, Tokuichi; Oka, Yuichiro; Kuroda, Kazuki; Iwata, Keiko; Kiyonari, Hiroshi; Matsuda, Shinji; Matsuzaki, Hideo; Yuzaki, Michisuke (13 March 2019)."PIP3-Phldb2 is crucial for LTP regulating synaptic NMDA and AMPA receptor density and PSD95 turnover".Scientific Reports.9(1): 4305.Bibcode:2019NatSR...9.4305X.doi:10.1038/s41598-019-40838-6.ISSN2045-2322.PMC6416313.PMID30867511.