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Trends Cancer. 2017 Mar;3(3):214-224. doi: 10.1016/j.trecan.2017.01.007. Epub 2017 Feb 18.

Calmodulin and PI3K Signaling in KRAS Cancers.

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Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, U.S.A.
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Children's Medical Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200127, China.
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, IL 60607, U.S.A.


Calmodulin (CaM) uniquely promotes signaling of oncogenic K-Ras; but not N-Ras or H-Ras. How CaM interacts with K-Ras and how this stimulates cell proliferation are among the most challenging questions in KRAS-driven cancers. Earlier data pointed to formation of a ternary complex consisting of K-Ras, PI3Kα and CaM. Recent data point to phosphorylated CaM binding to the SH2 domains of the p85 subunit of PI3Kα and activating it. Modeling suggests that the high affinity interaction between the phosphorylated CaM tyrosine motif and PI3Kα, can promote full PI3Kα activation by oncogenic K-Ras. Our up-to-date review discusses CaM's role in PI3K signaling at the membrane in KRAS-driven cancers. This is significant since it may help development of K-Ras-specific pharmacology.


K-Ras; calcium; drug discovery; phosphorylated tyrosine motif; plasma membrane; proliferation

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