“Phosphatidylinositol (3,4,5)-trisphosphate”的意思、由来-开放百科全书

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.

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. In many types of eukaryotic cells, the production of PtdIns(3,4,5)P₃ and recruitment of PH domain proteins to the membrane results in localized actin polymerization, leading to cellular protrusions that are important for cell migration, division, and phagocytosis.^[4]

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. ^{{cite journal | vauthors = Whitman M, Downes CP, Keeler M, Keller T, Cantley L | title = Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate | journal = Nature | volume = 332 | issue = 6165 | pages = 644–6 | date = April 1988 | pmid = 2833705 | doi = 10.1038/332644a0 }}
2. ^{{cite journal | vauthors = Traynor-Kaplan AE, Harris AL, Thompson BL, Taylor P, Sklar LA | title = An inositol tetrakisphosphate-containing phospholipid in activated neutrophils | journal = Nature | volume = 334 | issue = 6180 | pages = 353–6 | date = July 1988 | pmid = 3393226 | doi = 10.1038/334353a0 }}
3. ^{{cite journal | vauthors = Auger KR, Serunian LA, Soltoff SP, Libby P, Cantley LC | title = PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells | journal = Cell | volume = 57 | issue = 1 | pages = 167–75 | date = April 1989 | pmid = 2467744 | doi = 10.1016/0092-8674(89)90182-7 }}
4. ^{{cite journal | vauthors = Artemenko Y, Lampert TJ, Devreotes PN | title = Moving towards a paradigm: common mechanisms of chemotactic signaling in Dictyostelium and mammalian leukocytes | journal = Cellular and Molecular Life Sciences | volume = 71 | issue = 19 | pages = 3711–47 | date = October 2014 | pmid = 24846395 | pmc = 4162842 | doi = 10.1007/s00018-014-1638-8 }}