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Insights into the oncogenic effects of /PIK3CA/ mutations from the structure of p110α/p85α

Chuan-Hsiang Huang, Diana Mandelker, Sandra B. Gabelli and L. Mario Amzel

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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, PI3Kα, 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 PI3Kα, p110α, and a portion of its regulatory subunit, p85α 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

Chuan-Hsiang Huang

Johns Hopkins University School of Medicine; Baltimore, MD

Diana Mandelker

The Johns Hopkins Kimmel Cancer Center; Baltimore, MD

Sandra B. Gabelli

Johns Hopkins University School of Medicine; Baltimore, MD

L. Mario Amzel

Johns Hopkins University School of Medicine; Baltimore, MD

Purchase article for $19

Subscribe to this journal for $129/year