Somatic Akt1 mutation found in human cancers

The Akt1 (v-akt murine thymoma viral oncogene homolog 1) pathway has long been associated with the activation of survival and proliferation pathways in cancer. However, Akt1 activation was thought to be mediated by somatic mutations in other pathway members (e.g. PI(3)K) - not mutations in Akt1.

This article describes an Akt1 mutation (Akt(E17K)) found in human breast, colorectal, and ovarian cancers. Rather than the catalytic domain, the mutation resides in a domain responsible for Akt1 membrane localization - the PHD (pleckstrin homology domain).

The Akt(E17K) mutation alters Akt1 subcellular localization - from the cytoplasm to the membrane - causing increased activation of Akt1. This mutation was able to transform rat fibroblasts and induced leukemia in mice.

Membrane localization of Akt1 drives Akt1 activation and subsequent downstream activation of oncogenic pathways. Anti-cancer drugs that target the PHD domain of Akt1 could be designed to block Akt1 activation.

Carpten et al. 2007 [Nature]