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FBXO2-mediated KPTN ubiquitination promotes amino acid-dependent mTORC1 signaling and tumor growth

Jianfang Gao1, Jina Qing1, Xianglong Li1

  • 1Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Institute of Interdisciplinary Studies, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China.

The Journal of Clinical Investigation
|December 16, 2025
PubMed

Insights

FBXO2 targets KPTN for ubiquitination, disrupting the KICSTOR complex and promoting liver cancer. This discovery reveals a new mTORC1 signaling pathway and potential therapeutic targets for hepatocellular carcinoma (HCC).

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Oncology

Background:

  • Mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth; its dysregulation is linked to cancer.
  • The KICSTOR complex (KPTN, ITFG2, C12orf66, SZT2) negatively regulates amino acid-induced mTORC1 activation.
  • Regulatory mechanisms of KICSTOR are not well understood.

Purpose of the Study:

  • To identify key modulators of amino acid-dependent mTORC1 signaling.
  • To elucidate the role of FBXO2 in KICSTOR complex regulation.
  • To investigate the implications of FBXO2-KPTN interaction in hepatocellular carcinoma (HCC).

Main Methods:

  • Investigated protein-protein interactions between FBXO2 and KPTN using co-localization and direct interaction assays.
  • Analyzed KPTN ubiquitination status upon FBXO2 expression.
  • Assessed the impact of FBXO2-mediated KPTN ubiquitination on KICSTOR complex assembly and GATOR1 recruitment.
  • Examined FBXO2 protein levels in liver cancer patient samples and correlated with HCC progression.

Main Results:

  • FBXO2 directly interacts with KPTN and promotes its polyubiquitination at specific lysine residues.
  • FBXO2-mediated KPTN ubiquitination disrupts KICSTOR complex integrity by altering subunit interactions.
  • FBXO2 is upregulated in HCC, and its activity facilitates hepatocellular carcinoma progression.
  • FBXO2-induced KPTN ubiquitination impairs KICSTOR's ability to inhibit mTORC1 signaling.

Conclusions:

  • FBXO2 acts as a critical negative regulator of KICSTOR function through KPTN ubiquitination.
  • This FBXO2-KPTN axis represents a novel regulatory mechanism in amino acid-dependent mTORC1 signaling.
  • FBXO2 and KPTN ubiquitination are potential therapeutic targets for hepatocellular carcinoma (HCC).
Keywords:
Cell biologyLiver cancerOncologySignal transductionUbiquitin-proteosome system

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