Phosphatidylinositol (3,4,5)-trisphosphate

<h2 id="discovery">Discovery</h2>
In 1988, <a href="/facts/Lewis_C._Cantley/0gmCjB56">Lewis C. Cantley</a> published 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).<a class="footnote-ref" id="fnref:1" href="#fn:1">1</a> Working independently, Alexis Traynor-Kaplan and coworkers published a paper demonstrating that a novel lipid, phosphatidylinositol 3,4,5 trisphosphate (PIP3) occurs naturally in human <a href="/facts/Neutrophils/KL6oTt8b">neutrophils</a> with levels that increased rapidly following physiologic stimulation with chemotactic peptide.<a class="footnote-ref" id="fnref:2" href="#fn:2">2</a> Subsequent studies demonstrated that in vivo the enzyme originally identified by Cantley's group prefers PtdIns(4,5)P2 as a substrate, producing the product PIP3.<a class="footnote-ref" id="fnref:3" href="#fn:3">3</a>

<h2 id="function">Function</h2>
PIP3 functions to activate downstream signaling components, the most notable one being the protein kinase <a href="/facts/Protein_kinase_B/odL6duk1">Akt</a>, which activates downstream anabolic signaling pathways required for cell growth and survival.<a class="footnote-ref" id="fnref:4" href="#fn:4">4</a>
PtdIns(3,4,5)P3 is dephosphorylated by the <a href="/facts/Phosphatase/LBJs1fXx">phosphatase</a> <a href="/facts/PTEN_(gene)/Xg6MAcHm">PTEN</a> on the 3 position, generating <a href="/facts/PIP2/Sq6VS4vk">PI(4,5)P2</a>, and by SHIPs (SH2-containing inositol phosphatase) on the 5' position of the <a href="/facts/Inositol/FVon023Q">inositol</a> ring, producing <a href="/facts/Phosphatidylinositol_(3%2c4)-bisphosphate/oxAE3ng3">PI(3,4)P2</a>.<a class="footnote-ref" id="fnref:5" href="#fn:5">5</a> 
The <a href="/facts/PH_domain/0lqnQpg5">PH domain</a> in a number of proteins binds to PtdIns(3,4,5)P3. Such proteins include <a href="/facts/AKT/S0Dz4fkr">Akt/PKB</a>,<a class="footnote-ref" id="fnref:6" href="#fn:6">6</a> <a href="/facts/Phosphoinositide-dependent_kinase-1/LE1k8rQp">PDPK1</a>,<a class="footnote-ref" id="fnref:7" href="#fn:7">7</a> <a href="/facts/Bruton%2527s_tyrosine_kinase/6NCNAg20">Btk</a>1, and <a href="/facts/CYTH2/AwzDPVSD">ARNO</a>.<a class="footnote-ref" id="fnref:8" href="#fn:8">8</a>

<h2 id="roles-in-the-nervous-system">Roles in the nervous system</h2>
PIP3 plays a critical role outside the cytosol, notably at the postsynaptic terminal of hippocampal cells. Here, PIP3 has been implicated in regulating synaptic strengthening and AMPA expression, contributing to <a href="/facts/Long-term_potentiation/AbuJmBeo">long-term potentiation</a>. Moreover, PIP3 suppression disrupts normal AMPA expression on the neuron membrane and instead leads to the accumulation of AMPA on dendritic spines, commonly associated with synaptic depression.<a class="footnote-ref" id="fnref:9" href="#fn:9">9</a> 
PIP3 interacts with proteins to mediate <a href="/facts/Synaptic_plasticity/rdVFxItN">synaptic plasticity</a>. Of these proteins, Phldb2 has been shown to interact with PIP3 to induce and maintain long-term potentiation. In the absence of such an interaction, memory consolidation is impaired.<a class="footnote-ref" id="fnref:10" href="#fn:10">10</a>

<h2 id="references">References</h2>

<ol>
<li id="fn:1">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. PMID 2833705. S2CID 4326568. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></li>
<li id="fn:2">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. PMID 3393226. S2CID 4263472. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></li>
<li id="fn:3">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. PMID 2467744. S2CID 22154860. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></li>
<li id="fn:4">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. ISSN 1476-5403. PMC 6329745. PMID 29786068. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329745" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329745</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></li>
<li id="fn:5">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. ISSN 1540-8140. PMC 7480098. PMID 32673396. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480098" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480098</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></li>
<li id="fn:6">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. ISSN 1470-8752. PMID 26862211. <a href="https://research.monash.edu/files/226576341/3592704_oa.pdf" target="_blank">https://research.monash.edu/files/226576341/3592704_oa.pdf</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></li>
<li id="fn:7">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. ISSN 1096-3650. PMID 28473254. <a href="https://pubmed.ncbi.nlm.nih.gov/28473254/" target="_blank">https://pubmed.ncbi.nlm.nih.gov/28473254/</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></li>
<li id="fn:8">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. ISSN 0960-9822. PMID 9550703. S2CID 12974067. <a href="https://doi.org/10.1016%2Fs0960-9822%2898%2970181-2" target="_blank">https://doi.org/10.1016%2Fs0960-9822%2898%2970181-2</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></li>
<li id="fn:9">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. ISSN 1546-1726. PMC 2810846. PMID 20010819. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810846" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810846</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></li>
<li id="fn:10">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. ISSN 2045-2322. PMC 6416313. PMID 30867511. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416313" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416313</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></li>
</ol>

Phosphatidylinositol (3,4,5)-trisphosphate open-in-new

Phosphatidylinositol (3,4,5)-trisphosphate