Molecules in medicine mini-review: isoforms of PI3K in biology and disease

Abstract

The PI3K lipid kinases are involved in signal transduction and intracellular vesicular traffic, endowing these enzymes with multiple cellular functions and important roles in normal physiology and disease. In this mini-review, we aim to distil from the vast PI3K literature the key relevant concepts for successful targeting of this pathway in disease. Of the eight isoforms of PI3K, the class I PI3Ks have been implicated in the aetiology and maintenance of various diseases, most prominently cancer, overgrowth syndromes, thrombosis, inflammation and autoimmunity, with emerging potential roles in metabolic, cardiovascular and other disorders. The development of class I PI3K inhibitors, mainly for use in cancer and inflammatory disorders, is a very active area of drug development. In 2014, an inhibitor of the p110δ isoform of PI3K was approved for the treatment of some human B-cell malignancies. The key therapeutic indications of targeting each class I PI3K isoform are summarized and discussed.

PI3Kδ and primary immunodeficiencies

“…Although there is substantial potential for redundancy among the catalytic subunits, unique roles for each individual p110 isoform have been described, reflecting their different expression patterns as well as how they are engaged by their respective receptors8, 11. For example, p110α is activated by insulin-like receptors and regulates growth, metabolism and angiogenesis11, whereas p110β contributes to metabolic signalling and has been shown to regulate responses of mouse neutrophils to immune complexes 12, 13. P110γ is highly expressed in myeloid cells and contributes to chemotactic responses, as well as reactive oxygen species (ROS) production in neutrophils14.…”

Promotion of Tumor Invasion by Tumor-Associated Macrophages: The Role of CSF-1-Activated Phosphatidylinositol 3 Kinase and Src Family Kinase Motility Signaling

“…Macrophages express all three of them; the ubiquitously expressed p110α and p110β isoforms, and the hematopoietically expressed p110δ, and they have non-redundant biological roles [84,89,90]. Together, their activation triggers a plethora of signals to growth, survival, proliferation and migration by inducing the translocation of pleckstrin homology (PH) domain-containing molecules such as Akt/PKB [91,92].…”

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

“…They are classified into three classes based on the phosphorylated lipids generated. Class I PI3Ks catalyze the production of phosphatidylinositol-(3,4,5)-trisphosphate (PIP 3 ) from PIP 2 and are heterodimers comprising Kinase Inhibitors in Airway Disease a p110 catalytic subunit with four isoforms (designated P110a, b, g, and d) together with an adaptor subunit of either p85 (class IA) that are triggered by receptor tyrosine kinases (RTKs) and include PI3Ka, b, and d, or of p110/p84 (class IB) that are mainly triggered by G-protein-coupled receptors that include PI3Kg (Vanhaesebroeck et al, 2016). PIP 3 accumulates in the plasma membrane and recruits pleckstrin homology domain-containing proteins, including phosphoinositidedependent kinase-1 (PDK1) and Akt (also called protein kinase B).…”