Phosphoinositide 3-kinases (PI 3-kinases or PI3Ks) are a family of related enzymes that are capable of phosphorylating the 3 position hydroxyl group of the inositol ring of phosphatidylinositol (PtdIns)[1]. Hydroxyl group The term hydroxyl group is used to describe the functional group -OH when it is a substituent in an organic compound. ... Inositol, or cis-1,2,3,5-trans-4,6-cyclohexanehexol, is a cyclic polyalcohol that plays an important role as a second messenger in a cell, in the form of inositol phosphates. ... Phosphatidylinositol (PI), a phospholipid that is located in the plasma membrane. ...

The various 3-phosphorylated phosphoinositides that are produced by PI 3-kinases (PtdIns3P, PtdIns(3,4)P2, PtdIns(3,5)P2 and PtdIns(3,4,5)P3) function in a mechanism by which an assorted group of signalling proteins, containing Phox domains (PX domains), pleckstrin homology domains (PH domains), FYVE domains and other phosphoinositide-binding domains, are recruited to various cellular membranes.

In humans there are eight distinct catalytic PI 3-kinase subunits which are classified in three classes (Class I PI 3-kinases (EC 2.7.1.153 [2]), Class II PI 3-kinases (EC 2.7.1.154 [3]), and Class III PI 3-kinase (EC 2.7.1.137) [4]). The majority of the research on PI 3-kinases has focused on the Class I PI 3-kinases. Class I PI 3-kinases are composed of a catalytic subunit known as p110 and a regulatory subunit either related to p85 or p101. The p85 subunits contain SH2 and SH3 domains (OMIM 171833). Class III PI 3-kinases are also composed of a catalytic subunit Vps34 and a regulatory subunit p150 (Vps15 in yeast). Class III PI 3-kinase is a subgroup of the enzyme family, phosphoinositide 3-kinase that share a common protein domain structure, substrate specificity and method of activation. ... Ribbon diagram of the SH2 domain of human P56-Lck tyrosine kinase (PDB accession code 1LKK, chain A), colored from blue (N-terminus) to red (C-terminus). ... An SH3 domain is a protein module, a characteristic peptide sequence. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ...

All PI 3-kinases are inhibited by the drugs wortmannin and LY294002, although certain member of the class II PI 3-kinase family show decreased sensitivity. The introduction of this article does not provide enough context for readers unfamiliar with the subject. ...

Functions

PI 3-kinases have been linked to an extraordinarily diverse group of cellular functions, including cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. Many of these functions relate to the ablilty of class I PI 3-kinases to activate protein kinase B (PKB, aka Akt). The class IA PI 3-kinase p110α is mutated in many cancers. Many of these mutations cause the kinase to be more active. The PtdIns(3,4,5)P₃ phosphatase PTEN which antagonises PI 3-kinase signalling is absent from many tumours. Hence, PI 3-kinase activity contributes significantly to cellular transformation and the development of cancer. The p110δ and p110γ isoforms regulate different aspects of immune responses. PI 3-kinases are also a key component of the insulin signalling pathway. Hence there is great interest in the role of PI 3-kinase signalling in Diabetes mellitus. PTEN may mean: PTEN gene - one of the tumor suppressor gene (chromosome 10) Prime Time Entertainment Network ... When normal cells are damaged beyond repair, they are eliminated by apoptosis. ... For the disease characterized by excretion of large amounts of severely diluted urine, see diabetes insipidus. ...

PI 3-kinases as protein kinases

Many of the PI 3-kinases appear to have a serine/threonine kinase activity in vitro; however, it is unclear whether this has any role in vivo.

In addition to the class I – class III PI 3-kinases there are a group of more distantly related enzymes that are sometimes referred to as class IV PI 3-kinases. The class IV PI 3-kinases family is composed of ataxia telangiectasia mutated (ATM), ataxia telangiectasia related (ATR), DNA-dependent protein kinase (DNA-PK) and mammalian Target Of Rapamycin (mTOR). These members of the PI 3-kinase superfamily are protein serine/threonine kinases. Ataxia-telangiectasia mutated kinase is a serine threonine kinase that is recruited and activated by double stranded breaks of DNA and the MRN complex. ... The mammalian target of rapamycin is commonly known as mTOR. It is a serine/threonine kinase that regulates translation and cell division. ...

PI 3-kinases inhibitors as therapeutics

As wortmannin and LY294002 are broad inhibitors against PI 3-kinases and a number of unrelated proteins at higher concentrations they are too toxic to be used as therapeutics. A number of pharmaceutical companies have recently been working on PI 3-kinase isoform specific inhibitors including the class I PI 3-kinase, p110δ isoform specific inhibitors, IC486068 and IC87114, ICOS Corporation.

References

Vanhaesebroeck B et al. Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem. 2001;70:535-602. [5].