A kinase-independent function of AKT promotes cancer cell survival. Academic Article uri icon

Overview

abstract

  • The serine-threonine kinase AKT regulates proliferation and survival by phosphorylating a network of protein substrates. In this study, we describe a kinase-independent function of AKT. In cancer cells harboring gain-of-function alterations in MET, HER2, or Phosphatidyl-Inositol-3-Kinase (PI3K), catalytically inactive AKT (K179M) protected from drug induced cell death in a PH-domain dependent manner. An AKT kinase domain mutant found in human melanoma (G161V) lacked enzymatic activity in vitro and in AKT1/AKT2 double knockout cells, but promoted growth factor independent survival of primary human melanocytes. ATP-competitive AKT inhibitors failed to block the kinase-independent function of AKT, a liability that limits their effectiveness compared to allosteric AKT inhibitors. Our results broaden the current view of AKT function and have important implications for the development of AKT inhibitors for cancer.

publication date

  • December 31, 2014

Research

keywords

  • Cell Survival
  • Melanoma
  • Proto-Oncogene Proteins c-akt

Identity

PubMed Central ID

  • PMC4337624

Scopus Document Identifier

  • 84922891324

Digital Object Identifier (DOI)

  • 10.7554/eLife.03751

PubMed ID

  • 25551293

Additional Document Info

volume

  • 3