Phosphatidylinositol (3,4,5)-trisphosphate

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Phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol-3,4,5-trisphosphate.svg
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 their standard state (at 25 °C [77 °F], 100 kPa).
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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.

Contents

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]

Related Research Articles

<span class="mw-page-title-main">Phosphatidylinositol</span> Signaling molecule

Phosphatidylinositol or inositol phospholipid is a biomolecule. It was initially called "inosite" when it was discovered by Léon Maquenne and Johann Joseph von Scherer in the late 19th century. It was discovered in bacteria but later also found in eukaryotes, and was found to be a signaling molecule.

<span class="mw-page-title-main">Protein kinase B</span> Set of three serine threonine-specific protein kinases

Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration.

<span class="mw-page-title-main">Phosphoinositide phospholipase C</span>

Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. These enzymes belong to a larger superfamily of Phospholipase C. Other families of phospholipase C enzymes have been identified in bacteria and trypanosomes. Phospholipases C are phosphodiesterases.

<i>PTEN</i> (gene) Tumor suppressor gene

Phosphatase and tensin homolog (PTEN) is a phosphatase in humans and is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers, specifically glioblastoma, lung cancer, breast cancer, and prostate cancer. Genes corresponding to PTEN (orthologs) have been identified in most mammals for which complete genome data are available.

<span class="mw-page-title-main">Phosphoinositide 3-kinase</span> Class of enzymes

Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.

<span class="mw-page-title-main">Phosphatidylinositol 4,5-bisphosphate</span> Chemical compound

Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)P2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)P2 is enriched at the plasma membrane where it is a substrate for a number of important signaling proteins. PIP2 also forms lipid clusters that sort proteins.

<span class="mw-page-title-main">Phosphatidylinositol 3-phosphate</span> Chemical compound

Phosphatidylinositol 3-phosphate (PtdIns3P) is a phospholipid found in cell membranes that helps to recruit a range of proteins, many of which are involved in protein trafficking, to the membranes. It is the product of both the class II and III phosphoinositide 3-kinases activity on phosphatidylinositol.

<span class="mw-page-title-main">Phosphatidylinositol 3,4-bisphosphate</span>

Phosphatidylinositol (3,4)-bisphosphate is a minor phospholipid component of cell membranes, yet an important second messenger. The generation of PtdIns(3,4)P2 at the plasma membrane activates a number of important cell signaling pathways.

<span class="mw-page-title-main">Pleckstrin homology domain</span> Protein domain

Pleckstrin homology domain or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton.

<span class="mw-page-title-main">Phosphatidylinositol 3,5-bisphosphate</span> Chemical compound

Phosphatidylinositol 3,5-bisphosphate is one of the seven phosphoinositides found in eukaryotic cell membranes. In quiescent cells, the PtdIns(3,5)P2 levels, typically quantified by HPLC, are the lowest amongst the constitutively present phosphoinositides. They are approximately 3 to 5-fold lower as compared to PtdIns3P and PtdIns5P levels, and more than 100-fold lower than the abundant PtdIns4P and PtdIns(4,5)P2. PtdIns(3,5)P2 was first reported to occur in mouse fibroblasts and budding yeast S. cerevisiae in 1997. In S. cerevisiae PtdIns(3,5)P2 levels increase dramatically during hyperosmotic shock. The response to hyperosmotic challenge is not conserved in most tested mammalian cells except for differentiated 3T3L1 adipocytes.

Phosphatidylinositol phosphate kinases (PIPK) are kinases that phosphorylate the phosphoinositides PtdInsP and PtdInsP2 that are derivatives of phosphatidylinositol (PtdIns). It has been found that PtdIns is only phosphorylated on three (3,4,5) of its five hydroxyl groups, possibly because D-2 and D-6 hydroxyl groups cannot be phosphorylated because of steric hindrance. All 7 combinations of phosphorylated PtdIns have been found in animals, all except PtdIns(3,4,5)P3 have been found in plants.

<span class="mw-page-title-main">PX domain</span>

The PX domain is a phosphoinositide-binding structural domain involved in targeting of proteins to cell membranes.

The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.

Bisphosphate may refer to:

Phosphatidylinositol 5-phosphate (PtdIns5P) is a phosphoinositide, one of the phosphorylated derivatives of phosphatidylinositol (PtdIns), that are well-established membrane-anchored regulatory molecules. Phosphoinositides participate in signaling events that control cytoskeletal dynamics, intracellular membrane trafficking, cell proliferation and many other cellular functions. Generally, phosphoinositides transduce signals by recruiting specific phosphoinositide-binding proteins to intracellular membranes.

Lewis C. Cantley is an American cell biologist and biochemist who has made significant advances to the understanding of cancer metabolism. Among his most notable contributions are the discovery and study of the enzyme PI-3-kinase, now known to be important to understanding cancer and diabetes mellitus. He is currently Meyer Director and Professor of Cancer Biology at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine in New York City. He was formerly a professor in the Departments of Systems Biology and Medicine at Harvard Medical School, and the Director of Cancer Research at the Beth Israel Deaconess Medical Center, in Boston, Massachusetts. In 2016, he was elected Chairman of the Board for the Hope Funds for Cancer Research.

72 kDa inositol polyphosphate 5-phosphatase, also known as phosphatidylinositol-4,5-bisphosphate 5-phosphatase or Pharbin, is an enzyme that in humans is encoded by the INPP5E gene.

Leonard (Len) R Stephens FRS is a molecular biologist, senior group leader and associate director at the Babraham Institute.

Phillip (Phill) Thomas Hawkins FRS is a molecular biologist, senior group leader at the Babraham Institute.

Phosphatidylinositol-4-phosphate 5-kinases are a class of enzymes that phosphorylate phosphatidylinositol 4-phosphate. They perform this reaction on the fifth hydroxyl of the myo-inositol ring to form phosphatidylinositol 4,5-bisphosphate.

References

  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.