Phosphatidylinositol (PI) 4-kinase IIα (PI4KIIα) is the dominant PI4K in mammalian cells and plays important roles in membrane trafficking and signaling transduction. We report for the first time that PI4KIIα can promote the growth of multi-malignant tumors [1]. Our further study showed that PI4KIIα has pivotal role in the regulation of EGFR protein levels and combinatorial inhibition of PI4KIIα and EGFR showed strong anti-tumor effect [2]. To know the kinase activity regulation mechanism, we then solved the crystal structure of human PI4KIIα catalytic domain in its ADP-bound form at 2.95 Å resolution. Three novel insertions that are not present in other PIKs were found in PI4KIIα. The palmitoylation insertion and RK-rich insertion are critical for the regulation of PI4KIIα’s membrane binding and kinase activity. A distinct nucleotide-binding pocket of PI4KIIα was found that differs notably from that of PI3Ks, which well explained the insensitivity of PI4KIIα to PI3Ks’ inhibitors. Molecular dynamics stimulation, biochemical and mutagenesis studies reveal that any perturbation of the interaction between PI4KIIα and membrane will affect either the nucleotide binding or PI binding and then modulate the kinase activity of PI4KIIα [3]. Screening for a subtype specific inhibitor for PI4KIIα is undergoing.
[1] Li J, Lu Y, Zhang J, Kang H, Qin Z, Chen C. PI4K IIalpha is a novel regulator of tumor growth by its action on angiogenesis and HIF-1alpha regulation. Oncogene, 2010, 29: 2550-2559.
[2] Li J, Zhang L, Kang H, Chen C. Combinatorial inhibition of PI4KIIα and EGFR as novel anti-tumor strategy. Protein & Cell (in press, 2014)
[3] Zhou Q, Li J, Yu H, Zhai Y, Gao Z, Liu Y, Pang X, Zhang L, Schulten K, Sun F, Chen C. Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIalpha. Nat Commun, 2014, 5: 3552.