The mechanism of oncogenic PI3K lipid kinase variants at the membrane and their cryptic pockets.

ABSTRACT: The emergence of cancer requires at least two mutations. The mutational profiles of cancer-prone alleles often include hotspot mutations. A cancer hotspot combined with a weak/moderate mutation can result in significant deviation from hotspot-only variants, suggesting a graded clinical phenotypic spectrum. PI3Kα variants can carry both oncogenic mutations and mutations associated with benign tumors and neurodevelopmental disorders. Statistics on same-allele double mutations and their single components in PI3Kα support the "one-two punch" cancer emergence hypothesis, in which cancer hotspots can pair with low-frequency, weak or moderate mutations. Atomistic MD simulations revealed expanded conformational profiles of PI3Kα variants with single and double mutations. The combination of hotspot

SUBMITTER: Jang H 

PROVIDER: S-EPMC12262658 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature