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

58 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	R01CA135341
Frederick National Laboratory for Cancer Research
Government of South Australia

UN SDGs

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

Access to Document

10.1016/j.trecan.2017.01.007

Cite this

@article{91191a270ed34c418f6b93adc7da873f,

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",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = mar,

day = "1",

doi = "10.1016/j.trecan.2017.01.007",

language = "אנגלית",

volume = "3",

pages = "214--224",

journal = "Trends in Cancer",

issn = "2405-8033",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - Calmodulin and PI3K Signaling in KRAS Cancers

AU - Nussinov, Ruth

AU - Wang, Guanqiao

AU - Tsai, Chung Jung

AU - Jang, Hyunbum

AU - Lu, Shaoyong

AU - Banerjee, Avik

AU - Zhang, Jian

AU - Gaponenko, Vadim

PY - 2017/3/1

Y1 - 2017/3/1

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.

UR - http://www.scopus.com/inward/record.url?scp=85013073480&partnerID=8YFLogxK

U2 - 10.1016/j.trecan.2017.01.007

DO - 10.1016/j.trecan.2017.01.007

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.systematicreview???

AN - SCOPUS:85013073480

SN - 2405-8033

VL - 3

SP - 214

EP - 224

JO - Trends in Cancer

JF - Trends in Cancer

IS - 3

ER -

Calmodulin and PI3K Signaling in KRAS Cancers

Abstract

Funding

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this