Phosphoinositide 3-kinase

Phosphoinositide 3-kinases (PI3Ks) are a family of related intracellular signal transduction proteins that are involved in various cellular functions, including cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking. Many of these functions relate to the ability of class I PI3Ks to activate Protein kinase B (PKB), also known as Akt. PI3Ks are also implicated in the immune response.

Classification

PI3Ks are grouped into three classes based on their structure and substrate specificity:

• Class I PI3Ks are heterodimeric, consisting of a regulatory and a catalytic subunit. They are further divided into Class IA (which act on cells in response to growth factor stimulation) and Class IB (which are activated by G-protein-coupled receptors).
• Class II PI3Ks consist of a single catalytic subunit and are less understood. They seem to be involved in the regulation of vesicle trafficking and cellular metabolism.
• Class III PI3K is mainly involved in the regulation of vesicle trafficking and autophagy.

Function

PI3Ks phosphorylate the 3' hydroxyl group of the inositol ring of phosphatidylinositol lipids. The most well-studied reaction is the phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2) to phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 serves as a second messenger that recruits proteins to the cell membrane, including Akt.

Activation of Akt leads to the activation of several downstream signals that are important for cell survival and growth. This pathway is tightly regulated and is often dysregulated in cancer, making PI3Ks a target for cancer therapy.

Clinical Significance

Alterations in PI3K activity have been linked to a variety of diseases, including cancer, diabetes, and inflammation. PI3K signaling is often upregulated in cancer, leading to increased proliferation and survival of tumor cells. As such, inhibitors of PI3K are being actively developed as cancer therapeutics.

In diabetes, PI3K signaling is involved in the metabolic actions of insulin, and dysregulation of this pathway can contribute to insulin resistance.

PI3K Inhibitors

Several PI3K inhibitors are currently in clinical development for the treatment of cancer. These inhibitors can be broadly classified into pan-PI3K inhibitors, which target multiple PI3K class I isoforms, and isoform-specific inhibitors, which target a single PI3K isoform.

See Also

• Akt
• Signal transduction
• Cancer
• Diabetes
• Insulin resistance