PI3Kd Human

Class IA PI3Ks consist of a catalytic subunit (p110) and a regulatory subunit (p85). The p110 subunit has three isoforms: p110α, p110β, and p110δ. The p85 subunit also has multiple isoforms, including p85α, p55α, p50α, p85β, and p55γ . The p110δ isoform, in particular, is predominantly expressed in leukocytes and is involved in immune responses .

The p110δ/p85α complex is a heterodimer where the p110δ catalytic subunit interacts with the p85α regulatory subunit. This interaction is crucial for the regulation of the kinase activity of p110δ. The p85α subunit contains SH2 (Src Homology 2) domains that bind to phosphorylated tyrosine residues on receptor tyrosine kinases (RTKs) or other adaptor proteins, leading to the recruitment of the p110δ/p85α complex to the plasma membrane . Upon membrane recruitment, the p110δ subunit phosphorylates phosphatidylinositol (4,5)-bisphosphate (PIP2) to generate phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which acts as a second messenger to activate downstream signaling pathways .

The human recombinant p110δ/p85α complex is typically expressed in baculovirus-infected insect cells. This system allows for the production of high-quality, active enzyme complexes that are suitable for biochemical and structural studies . The recombinant complex is often used to study enzyme kinetics, screen inhibitors, and profile selectivity .

The p110δ isoform is upregulated in certain leukemias, such as chronic lymphocytic leukemia (CLL), and is a target for specific inhibitors like CAL-101 (Idelalisib), which has shown promise in clinical trials . The unique regulatory mechanisms of p110δ, as compared to other isoforms like p110α and p110β, make it an attractive target for therapeutic intervention .