Phosphorylated Calmodulin Promotes PI3K Activation by Binding to the SH₂ Domains

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Calmodulin (CaM) plays a critical role in KRAS-driven cancers by stimulating PI3Kα/Akt signaling.
• Phosphorylation of CaM at Tyr99 (pY99) enhances PI3Kα activation, a key lipid kinase involved in cell growth and proliferation.
• PI3Kα comprises regulatory p85 and catalytic p110 subunits.

Purpose of the Study:

• To elucidate the mechanism by which phosphorylated CaM (pCaM) interacts with and activates PI3Kα.
• To investigate the role of pCaM's Tyr99 phosphorylation in PI3Kα activation.
• To understand the interplay between pCaM, K-Ras4B, and PI3Kα at the cell membrane.

Main Methods:

• Explicit-solvent molecular dynamics (MD) simulations were employed to study pCaM-PI3Kα interactions.
• Analysis focused on the binding of pCaM to the SH2 domains (nSH2 and cSH2) of the p85 subunit.
• Investigated conformational changes in CaM upon binding to K-Ras4B and PI3Kα.

Main Results:

• pCaM forms stable interactions with both nSH2 and cSH2 domains of p85, with pY99 being crucial.
• nSH2 prefers an extended pCaM conformation, while cSH2 prefers a collapsed conformation.
• The extended pCaM conformation bound to nSH2 releases p110 autoinhibition, representing a key PI3Kα activation step.

Conclusions:

• pCaM binding to nSH2 is the primary mechanism for PI3Kα activation in KRAS-driven cancers.
• K-Ras4B allosterically activates p110 independently, with membrane localization enhancing PI3Kα-K-Ras4B interactions.
• This study reveals detailed molecular interactions driving PI3Kα activation crucial for cancer cell proliferation.