Calmodulin and IQGAP1 activation of PI3Kα and Akt in KRAS, HRAS and NRAS-driven cancers.

Abstract

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-PI3Kα ternary complex promotes full PI3Kα activation, and thereby potent PI3Kα/Akt/mTOR proliferative signaling. CaM binds PI3Kα 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 PI3Kα. Activated, membrane-bound PI3Kα generates PIP3. 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, PI3Kα 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 PI3Kα/Akt/mTOR pathway at the membrane and innovate drug discovery, including blocking the PI3Kα-IQGAP1 interaction in HRAS- and NRAS-driven cancers.

• Authors: Ruth Nussinov, Mingzhen Zhang, Chung-Jung Tsai, Hyunbum Jang
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1864 Issue 6 Pt B Pg. 2304-2314 (Jun 2018) ISSN: 0925-4439 [Print] Netherlands
• PMID: 29097261 (Publication Type: Journal Article, Legal Case, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Review)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Calmodulin
• IQ motif containing GTPase activating protein 1
• KRAS protein, human
• Membrane Proteins
• ras GTPase-Activating Proteins
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• GTP Phosphohydrolases
• NRAS protein, human
• HRAS protein, human
• Proto-Oncogene Proteins p21(ras)

Topics

• Calmodulin (genetics, metabolism)
• Enzyme Activation (genetics)
• GTP Phosphohydrolases (genetics, metabolism)
• Humans
• Membrane Proteins (genetics, metabolism)
• Neoplasms (enzymology, genetics, pathology)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• Signal Transduction
• ras GTPase-Activating Proteins (genetics, metabolism)