Phosphatidylinositol (3,4,5)-trisphosphate

Phosphatidylinositol (3,4,5)-trisphosphate

Names
Other names PI(3,4,5)P3, PtdIns(3,4,5)P3
Properties
Chemical formula	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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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

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. Phospholipase C cleaves PIP₂ to produce inositol triphosphate IP3, and diacylglycerol.

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

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.