Calmodulin and IQGAP1 activation of PI3K alpha and Akt in KRAS, HRAS and NRAS-driven cancers

Calmodulin (CaM) binds only oncogenic KRas, but not HRas or NRas, and thus contributes only to KRAS-driven cancers. How CaM interacts with KRas and how it boosts KRAS cancers are among the most coveted aims in cancer biology. Here we address this question, and further ask: Are there proteins that can substitute for CaM in HRAS- and NRAS-driven cancers? Can scaffolding protein IQGAP1 be one? Data suggest that formation of a CaM-KRas-PI3K alpha ternary complex promotes full PI3K alpha activation, and thereby potent PI3K alpha/Akt/mTOR proliferative signaling. CaM binds PI3K alpha at the cSH2 and nSH2 domains of its regulatory p85 subunit; the WW domain of IQGAP1 binds cSH2. This raises the question whether IQGAP1, together with an oncogenic Ras isoform, can partially activate PI3K alpha. Activated, membrane-bound PI3K alpha generates PIPS. CaM shuttles Akt to the plasma membrane; CaM's release and concomitant phosphoinositide binding stimulates Akt activation. Notably, IQGAP1 directly interacts with, and helps juxtapose, PI3K alpha and Akt as well as mTOR. Our mechanistic review aims to illuminate CaM's actions, and help decipher how oncogenic Ras isoforms not only KRas4B can activate the PI3K alpha/Akt/mTOR pathway at the membrane and innovate drug discovery, including blocking the PI3K alpha IQGAP1 interaction in HRAS- and NRAS-driven cancers.

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