Structural effects of oncogenic PI3Kα mutations.
Physiological activation of PI3Kα is brought about by the release of the inhibition by p85 when the nSH2 binds the phosphorylated tyrosine of activated receptors or their substrates. Oncogenic mutations of PI3Kα result in a constitutively activated enzyme that triggers downstream pathways that increase tumor aggressiveness and survival. Structural information suggests that some mutations also activate the enzyme by releasing p85 inhibition. Other mutations work by different mechanisms. For example, the most common mutation, His1047Arg, causes a conformational change that increases membrane association resulting in greater accessibility to the substrate, an integral membrane component. These effects are examples of the subtle structural changes that result in increased activity. The structures of these and other mutants are providing the basis for the design of isozyme-specific, mutation-specific inhibitors for individualized cancer therapies.
Gabelli
Sandra B
SB
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. gabelli@jhmi.edu
Huang
Chuan-Hsiang
CH
Mandelker
Diana
D
Schmidt-Kittler
Oleg
O
Vogelstein
Bert
B
Amzel
L Mario
LM
D000595:Amino Acid Sequence; D058534:Class I Phosphatidylinositol 3-Kinases; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000235:genetics*
D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human