Phosphorylated Calmodulin Promotes PI3K Activation by Binding to the SH₂ Domains.

ABSTRACT: How calmodulin (CaM) acts in KRAS-driven cancers is a vastly important question. CaM binds to and stimulates PI3Kα/Akt signaling, promoting cell growth and proliferation. Phosphorylation of CaM at Tyr⁹⁹ (pY99) enhances PI3Kα activation. PI3Kα is a lipid kinase. It phosphorylates PIP₂ to produce PIP₃, to which Akt binds. PI3Kα has two subunits: the regulatory p85 and the catalytic p110. Here, exploiting explicit-solvent MD simulations we unveil key interactions between phosphorylated CaM (pCaM) and the two SH2 domains in the p85 subunit, confirm experimental observations, and uncover PI3Kα's mechanism of activation. pCaMs form strong and stable interactions with both nSH2 and cSH2 domains, with pY99 being the dominant contributor. Despite the high structural

SUBMITTER: Zhang M 

PROVIDER: S-EPMC5685777 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature