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Disruption of PH-kinase domain interactions leads to oncogenic activation of AKT in human cancers

Chaitali Parikh1, Vasantharajan Janakiraman, Wen-I Wu

  • 1Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.

Proceedings of the National Academy of Sciences of the United States of America
|November 9, 2012
PubMed

Insights

Mutations at the PH-KD interface of AKT (v-akt murine thymoma viral oncogene homolog) can cause constitutive activation, contributing to cancer. These AKT mutants are resistant to certain inhibitors, impacting cancer therapy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • The protein kinase AKT is crucial for cell survival and proliferation.
  • Hyperactivation of AKT is common in human cancers.
  • Intramolecular interactions between the pleckstrin homology (PH) domain and kinase domain (KD) maintain AKT in an inactive state.

Purpose of the Study:

  • To investigate the role of PH-KD interface interactions in AKT autoinhibition.
  • To identify novel mechanisms of AKT activation in cancer.
  • To assess the therapeutic implications of AKT mutations at the PH-KD interface.

Main Methods:

  • Site-directed mutagenesis to create mutations at the PH-KD interface.
  • Biochemical assays to assess AKT activity.
  • Analysis of AKT1 somatic mutations in human cancer samples.
  • Evaluation of AKT inhibitor efficacy against mutated AKT forms.

Main Results:

  • Most PH-KD interface mutations result in constitutive AKT activation.
  • Novel somatic mutations in AKT1 at the PH-KD interface were identified in human cancers.
  • AKT1 mutants exhibit constitutive activity, driving oncogenic signaling.
  • AKT1 mutants are not effectively inhibited by allosteric AKT inhibitors.

Conclusions:

  • Disruption of the PH-KD interface is a mechanism for AKT activation in cancer.
  • Identified AKT1 mutants have oncogenic potential and therapeutic relevance.
  • The efficacy of allosteric AKT inhibitors is dependent on an intact PH-KD interface.

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