Insights into the oncogenic effects of PIK3CA mutations from the structure of p110alpha/p85alpha.
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, PI3Kalpha, 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 PI3Kalpha, p110alpha, and a portion of its regulatory subunit, p85alpha 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.
Huang
Chuan-Hsiang
CH
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Mandelker
Diana
D
Gabelli
Sandra B
SB
Amzel
L Mario
LM
D000818:Animals; D020134:Catalytic Domain / Q000235:genetics; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D019281:Dimerization; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport / Q000502:physiology
D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human