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Title: Insights into the oncogenic effects of /PIK3CA/ mutations from the structure of p110[alpha]/p85[alpha]

Abstract

Phosphatidylinositide-3-kinases (PI3K) initiate a number of signaling pathways by recruiting other kinases, such as Akt, to the plasma membrane. One of the isoforms, PI3K{alpha}, is an oncogene frequently mutated in several cancer types. These mutations increase PI3K kinase activity, leading to increased cell survival, cell motility, cell metabolism, and cell cycle progression. The structure of the complex between the catalytic subunit of PI3K{alpha}, p110{alpha}, and a portion of its regulatory subunit, p85{alpha} reveals that the majority of the oncogenic mutations occur at the interfaces between p110 domains and between p110 and p85 domains. At these positions, mutations disrupt interactions resulting in changes in the kinase domain that may increase enzymatic activity. The structure also suggests that interaction with the membrane is mediated by one of the p85 domains (iSH2). These findings may provide novel structural loci for the design of new anti-cancer drugs.

Authors:
; ; ;  [1]
  1. (JHU)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1019131
Resource Type:
Journal Article
Journal Name:
Cell Cycle
Additional Journal Information:
Journal Volume: 7; Journal Issue: (9) ; 05, 2008
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; CELL CYCLE; DESIGN; MEMBRANES; METABOLISM; MUTATIONS; NEOPLASMS; ONCOGENES; PHOSPHOTRANSFERASES; PLASMA

Citation Formats

Huang, Chuan-Hsiang, Mandelker, Diana, Gabelli, Sandra B., and Amzel, L.Mario. Insights into the oncogenic effects of /PIK3CA/ mutations from the structure of p110[alpha]/p85[alpha]. United States: N. p., 2011. Web. doi:10.4161/cc.7.9.5817.
Huang, Chuan-Hsiang, Mandelker, Diana, Gabelli, Sandra B., & Amzel, L.Mario. Insights into the oncogenic effects of /PIK3CA/ mutations from the structure of p110[alpha]/p85[alpha]. United States. doi:10.4161/cc.7.9.5817.
Huang, Chuan-Hsiang, Mandelker, Diana, Gabelli, Sandra B., and Amzel, L.Mario. Thu . "Insights into the oncogenic effects of /PIK3CA/ mutations from the structure of p110[alpha]/p85[alpha]". United States. doi:10.4161/cc.7.9.5817.
@article{osti_1019131,
title = {Insights into the oncogenic effects of /PIK3CA/ mutations from the structure of p110[alpha]/p85[alpha]},
author = {Huang, Chuan-Hsiang and Mandelker, Diana and Gabelli, Sandra B. and Amzel, L.Mario},
abstractNote = {Phosphatidylinositide-3-kinases (PI3K) initiate a number of signaling pathways by recruiting other kinases, such as Akt, to the plasma membrane. One of the isoforms, PI3K{alpha}, is an oncogene frequently mutated in several cancer types. These mutations increase PI3K kinase activity, leading to increased cell survival, cell motility, cell metabolism, and cell cycle progression. The structure of the complex between the catalytic subunit of PI3K{alpha}, p110{alpha}, and a portion of its regulatory subunit, p85{alpha} reveals that the majority of the oncogenic mutations occur at the interfaces between p110 domains and between p110 and p85 domains. At these positions, mutations disrupt interactions resulting in changes in the kinase domain that may increase enzymatic activity. The structure also suggests that interaction with the membrane is mediated by one of the p85 domains (iSH2). These findings may provide novel structural loci for the design of new anti-cancer drugs.},
doi = {10.4161/cc.7.9.5817},
journal = {Cell Cycle},
number = (9) ; 05, 2008,
volume = 7,
place = {United States},
year = {2011},
month = {7}
}