Calmodulin and PI3K Signaling in KRAS Cancers

Ruth Nussinov; Guanqiao Wang; Chung Jung Tsai; Hyunbum Jang; Shaoyong Lu; Avik Banerjee; Jian Zhang; Vadim Gaponenko

doi:10.1016/j.trecan.2017.01.007

Calmodulin and PI3K Signaling in KRAS Cancers

Ruth Nussinov^*, Guanqiao Wang, Chung Jung Tsai, Hyunbum Jang, Shaoyong Lu, Avik Banerjee, Jian Zhang, Vadim Gaponenko

^*Corresponding author for this work

Human Molecular Genetics Biochemistry

Research output: Contribution to journal › Review article › peer-review

63 Scopus citations

Abstract

Calmodulin (CaM) uniquely promotes signaling by oncogenic K-Ras, but not by 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 the formation of a ternary complex consisting of K-Ras, phosphatidylinositide-3-kinase α (PI3Kα), and CaM. Recent data indicate that phosphorylated CaM binds to the Src homology 2 (SH2) domains of the p85 subunit of PI3Kα and activates 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. This review discusses the role of CaM in PI3K signaling at the membrane in KRAS-driven cancers. This is significant because it may help the development of K-Ras-specific pharmacology.

Original language	English
Pages (from-to)	214-224
Number of pages	11
Journal	Trends in Cancer
Volume	3
Issue number	3
DOIs	https://doi.org/10.1016/j.trecan.2017.01.007
State	Published - 1 Mar 2017

Funding

Funders	Funder number
National Institutes of Health	HHSN261200800001E
U.S. Department of Health and Human Services
American Cancer Society	RGS-09-057-01-GMC
National Cancer Institute	R01 CA135341, ZIABC010441
Frederick National Laboratory for Cancer Research
Government of South Australia

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.trecan.2017.01.007

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title = "Calmodulin and PI3K Signaling in KRAS Cancers",

abstract = "Calmodulin (CaM) uniquely promotes signaling by oncogenic K-Ras, but not by 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 the formation of a ternary complex consisting of K-Ras, phosphatidylinositide-3-kinase α (PI3Kα), and CaM. Recent data indicate that phosphorylated CaM binds to the Src homology 2 (SH2) domains of the p85 subunit of PI3Kα and activates 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. This review discusses the role of CaM in PI3K signaling at the membrane in KRAS-driven cancers. This is significant because it may help the development of K-Ras-specific pharmacology.",

author = "Ruth Nussinov and Guanqiao Wang and Tsai, {Chung Jung} and Hyunbum Jang and Shaoyong Lu and Avik Banerjee and Jian Zhang and Vadim Gaponenko",

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AU - Tsai, Chung Jung

AU - Jang, Hyunbum

AU - Lu, Shaoyong

AU - Banerjee, Avik

AU - Zhang, Jian

AU - Gaponenko, Vadim

PY - 2017/3/1

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N2 - Calmodulin (CaM) uniquely promotes signaling by oncogenic K-Ras, but not by 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 the formation of a ternary complex consisting of K-Ras, phosphatidylinositide-3-kinase α (PI3Kα), and CaM. Recent data indicate that phosphorylated CaM binds to the Src homology 2 (SH2) domains of the p85 subunit of PI3Kα and activates 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. This review discusses the role of CaM in PI3K signaling at the membrane in KRAS-driven cancers. This is significant because it may help the development of K-Ras-specific pharmacology.

AB - Calmodulin (CaM) uniquely promotes signaling by oncogenic K-Ras, but not by 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 the formation of a ternary complex consisting of K-Ras, phosphatidylinositide-3-kinase α (PI3Kα), and CaM. Recent data indicate that phosphorylated CaM binds to the Src homology 2 (SH2) domains of the p85 subunit of PI3Kα and activates 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. This review discusses the role of CaM in PI3K signaling at the membrane in KRAS-driven cancers. This is significant because it may help the development of K-Ras-specific pharmacology.

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Calmodulin and PI3K Signaling in KRAS Cancers

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UN SDGs

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