Phosphoinositide 3-kinase

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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].

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 (Mendelian Inheritance in Man (OMIM) 171833). Class III PI 3-kinases are also composed of a catalytic subunit Vps34 and a regulatory subunit p150 (Vps15 in yeast).

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.

1 Functions
2 PI 3-kinases as protein kinases
3 PI 3-kinases inhibitors as therapeutics
4 References

[edit] 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.

AKT is activated as a result of PI3-kinase activity, because Akt requires the formation of the PtdIns(3,4,5)P3 (or "PIP3") molecule in order to be translocated to the cell membrane. At PIP3, Akt is then phosphorylated by another kinase called PDK1, and is thereby activated. The "PI3-k/Akt" signaling pathway has been shown to be required for an extremely diverse array of cellular activities - most notably cellular proliferation and survival.

In addition to Akt and PDK1, one other related serine threonine kinase is bound at the PIP3 molecule created as a resulte of PI3-kinase activity, SGK.

[edit] 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 is 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.

[edit] 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.