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Updated: Jul 26, 2025

Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
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Cathepsin K inhibition induces Raptor destabilization and mitochondrial dysfunction via Syk/SHP2/Src/OTUB1

Seung Un Seo1, Seon Min Woo1, Taeg Kyu Kwon2,3

  • 1Department of Immunology, School of Medicine, Keimyung University, Daegu, 42601, South Korea.

Cell Death & Disease
|June 17, 2023
PubMed

Insights

The study reveals how inhibiting cathepsin K impacts the Raptor pathway in cancer. It identifies a Syk/SHP2/Src/OTUB1 signaling axis that could be a therapeutic target for cancer management.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The Raptor signaling pathway is crucial in cancer progression.
  • Src-mediated phosphorylation of OTUB1-Y26 stabilizes Raptor.
  • Cathepsin K inhibition (odanacatib; ODN) destabilizes Raptor, but mechanisms are unclear.

Purpose of the Study:

  • To elucidate the mechanisms of cathepsin K inhibition-induced OTUB1-Y26 phosphorylation and Raptor stabilization.
  • To investigate the role of SHP2 and Syk in this pathway.
  • To explore the impact on mitochondrial function.

Main Methods:

  • Utilized SHP2 deletion and pharmacological inhibition.
  • Investigated spleen tyrosine kinase (Syk) phosphorylation.
  • Assessed mitochondrial reactive oxygen species (ROS), fusion, and dysfunction.

Main Results:

  • Cathepsin K inhibition activates SHP2, dephosphorylating OTUB1 and destabilizing Raptor.
  • SHP2 deletion increases OTUB1-Y26 phosphorylation and Raptor expression.
  • Cathepsin K inhibition activates Syk, leading to SHP2-mediated OTUB1-Y26 dephosphorylation and mitochondrial dysfunction.

Conclusions:

  • Syk is an upstream kinase activating SHP2, regulating ODN-induced Raptor downregulation and mitochondrial dysfunction.
  • The Syk/SHP2/Src/OTUB1 signaling axis represents a potential therapeutic target in cancer.

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