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Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation

S Kuninaka1, S-I Iida, T Hara

  • 1Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto, Japan. hsaya@gpo.kumamoto-u.ac.jp

Oncogene
|November 30, 2006
PubMed

Insights

The serine protease Omi/HtrA2 processes WARTS (WTS)/large tumor-suppressor 1, revealing a novel role beyond apoptosis. This Omi-WTS interaction regulates cell cycle progression at interphase, impacting homeostasis.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Background:

  • The serine protease Omi/HtrA2 was initially identified as a proapoptotic factor.
  • Emerging evidence suggests Omi/HtrA2 also plays a role in cellular homeostasis, but its targets in this process remain unknown.
  • WARTS (WTS)/large tumor-suppressor 1 was previously shown to interact with and promote Omi/HtrA2 protease activity.

Purpose of the Study:

  • To investigate whether WARTS (WTS)/large tumor-suppressor 1 is a substrate of Omi/HtrA2.
  • To elucidate the role of Omi/HtrA2-mediated WTS processing in cellular processes beyond apoptosis.
  • To determine the impact of Omi/HtrA2 and WTS on cell cycle regulation.

Main Methods:

  • Co-immunoprecipitation to study protein interactions.
  • Protease assays to assess Omi/HtrA2 activity.
  • Cell proliferation assays and cell cycle analysis in Omi/HtrA2-depleted cells and WTS-depleted cells.
  • Treatment of caspase-9-deficient mouse embryonic fibroblasts (MEFs) with staurosporine.

Main Results:

  • WARTS (WTS)/large tumor-suppressor 1 is a direct substrate of Omi/HtrA2 protease activity.
  • Omi/HtrA2-mediated proteolysis of WTS can occur independently of apoptosis induction.
  • Depletion of Omi/HtrA2 or WTS leads to accelerated cell proliferation, suggesting a role in negative regulation of cell cycle progression at interphase.
  • Omi/HtrA2-mediated processing of WTS may generate fragments that inhibit G1/S phase transition.

Conclusions:

  • WARTS (WTS)/large tumor-suppressor 1 is both a regulator and a downstream target of Omi/HtrA2.
  • Omi/HtrA2 protease activity and WTS proteolysis are not exclusively linked to apoptosis.
  • Omi/HtrA2-mediated processing of WTS represents a novel mechanism for the negative regulation of cell cycle progression, highlighting a function beyond its apoptotic role.

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