Phosphatidylinositol (3,4,5)-trisphosphate

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Phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol-3,4,5-trisphosphate.svg
Properties
Molecular formula C47H86O22P4
Molar mass 1126.46 g/mol, neutral with fatty acid composition - 18:0, 20:4
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
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Infobox references

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[edit]

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[edit]

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.

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.

The PH domain in a number of proteins binds to PtdIns(3,4,5)P3. Such proteins include Akt/PKB, PDK1, Btk1, and ARNO. The generation of PtdIns(3,4,5)P3 at the plasma membrane upon the activation of class I PI 3-kinases causes these proteins to translocate to the plasma membrane and affects their activity accordingly.

The PH domain allows binding between PtdIns(3,4,5)P3 and G protein-coupled receptor kinases (GRKs). This enhances the binding of the GRK to the plasma membrane.

References[edit]

  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. doi:10.1038/332644a0. PMID 2833705. 
  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): 353–356. doi:10.1038/334353a0. PMID 3393226. 
  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.