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Identification of XAF1 as an endogenous AKT inhibitor

Min Chen1, Kangjunjie Wang2, Ying Han3

  • 1State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.

Cell Reports
|June 29, 2023
PubMed

Insights

XIAP-associated factor (XAF1) directly inhibits AKT1 kinase activation by blocking its ubiquitination. XAF1 deficiency promotes AKT activation, impacting metabolism and prostate cancer development.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Biology

Background:

  • AKT kinase is crucial for cell metabolism and survival, with tightly regulated activation.
  • Dysregulated AKT signaling is implicated in metabolic disorders and cancer.

Purpose of the Study:

  • To identify novel regulators of AKT1 kinase activity.
  • To investigate the role of XAF1 in AKT signaling and its implications in metabolic diseases and prostate cancer.

Main Methods:

  • Co-immunoprecipitation to identify interacting proteins.
  • Western blotting to assess protein ubiquitination and phosphorylation.
  • Gene knockout and ectopic expression studies in mouse models.
  • Analysis of human prostate cancer samples.

Main Results:

  • XAF1 directly binds AKT1, inhibiting its K63-linked poly-ubiquitination and activation.
  • Xaf1 knockout leads to AKT activation in mouse tissues, reducing diet-induced obesity and insulin resistance.
  • Reduced XAF1 expression correlates with increased p-AKT in prostate cancer, and Xaf1 deficiency accelerates tumor growth in mice.
  • XAF1 forms a negative feedback loop with AKT1 via FOXO1 transcriptional regulation.

Conclusions:

  • XAF1 acts as a novel negative regulator of AKT1 signaling.
  • Modulating XAF1 levels has therapeutic potential for metabolic diseases and prostate cancer.
Keywords:
AKTCP: Cell biologyFOXO1XAF1metabolismphosphorylationprostate cancerubiquitination

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