Phosphatidylinositol (3,4,5)-trisphosphate explained

Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid that resides on the plasma membrane.

Discovery

In 1988, Lewis C. Cantley 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).[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 human neutrophils with levels that increased rapidly following physiologic stimulation with chemotactic peptide.[2] 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.[3]

Function

PIP3 functions to activate downstream signaling components, the most notable one being the protein kinase Akt, which activates downstream anabolic signaling pathways required for cell growth and survival.[4]

PtdIns(3,4,5)P3 is dephosphorylated by the phosphatase PTEN on the 3 position, generating PI(4,5)P2, and by SHIPs (SH2-containing inositol phosphatase) on the 5' position of the inositol ring, producing PI(3,4)P2.[5]

The PH domain in a number of proteins binds to PtdIns(3,4,5)P3. Such proteins include Akt/PKB,[6] PDPK1,[7] Btk1, and ARNO.[8]

Roles in the nervous system

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 long-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 with synaptic depression.[9]

PIP3 interacts with proteins to mediate synaptic plasticity. 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.[10]

Notes and References

  1. Whitman M, Downes CP, Keeler M, Keller T, Cantley L . Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate . Nature . 332 . 6165 . 644–6 . April 1988 . 2833705 . 10.1038/332644a0 . 1988Natur.332..644W . 4326568 .
  2. Traynor-Kaplan AE, Harris AL, Thompson BL, Taylor P, Sklar LA . An inositol tetrakisphosphate-containing phospholipid in activated neutrophils . Nature . 334 . 6180 . 353–6 . July 1988 . 3393226 . 10.1038/334353a0 . 1988Natur.334..353T . 4263472 .
  3. Auger KR, Serunian LA, Soltoff SP, Libby P, Cantley LC . PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells . Cell . 57 . 1 . 167–75 . April 1989 . 2467744 . 10.1016/0092-8674(89)90182-7 . 22154860 .
  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. 10.1038/s41418-018-0121-8. 1476-5403. 6329745. 29786068.
  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. 10.1083/jcb.201910041. 1540-8140. 7480098. 32673396.
  6. Eramo. Matthew J.. Mitchell. Christina A.. February 2016. Regulation of PtdIns(3,4,5)P3/Akt signalling by inositol polyphosphate 5-phosphatases. Biochemical Society Transactions. 44. 1. 240–252. 10.1042/BST20150214. 1470-8752. 26862211.
  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. 10.1016/j.semcancer.2017.04.014. 1096-3650. 28473254.
  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. en. 8. 8. 463–466. 10.1016/s0960-9822(98)70181-2. 0960-9822. 9550703. 12974067. free. 1998CBio....8..463V .
  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. 10.1038/nn.2462. 1546-1726. 2810846. 20010819.
  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. 10.1038/s41598-019-40838-6. 2045-2322. 6416313. 30867511. 2019NatSR...9.4305X.

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