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P62/SQSTM1 mediates the autophagy-lysosome degradation of CDK2 protein undergoing PI3Kα/AKT T308 inhibition

Chao Zhang1, Hong-Liang Zhang2, Shan-Ling Liu3

  • 1Department of Geriatrics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201999, China; Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, China.

Biochemical and Biophysical Research Communications
|August 25, 2022
PubMed

Insights

Inactive CDK2 protein is degraded via the autophagy-lysosome pathway, not the ubiquitin proteasome pathway. This degradation is mediated by PI3Kα/AKT inhibition and involves P62/SQSTM1 binding.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Cyclin-dependent kinase 2 (CDK2) regulates cell cycle progression.
  • The degradation pathway of inactive CDK2 after cyclin dissociation is not well understood.
  • Existing knowledge focuses on the ubiquitin proteasome pathway for cyclin degradation.

Purpose of the Study:

  • To elucidate the degradation mechanism of inactive CDK2 protein.
  • To identify the specific pathway involved in CDK2 protein turnover.
  • To explore novel regulatory strategies for CDK2 protein levels.

Main Methods:

  • Serum starvation to induce G0/G1 phase arrest.
  • Analysis of CDK2 mRNA and protein levels.
  • Pharmacological inhibition of PI3K and AKT pathways.
  • Gene knockout techniques.
  • Immunoprecipitation to study protein interactions (P62/SQSTM1 binding).

Main Results:

  • CDK2 protein levels decreased during serum starvation without changes in mRNA.
  • CDK2 degradation was found to occur through the autophagy-lysosome pathway.
  • Inhibition of PI3Kα/AKTT308 mediated CDK2 degradation.
  • P62/SQSTM1 acts as an adaptor protein, binding to inactive CDK2 for autophagy-lysosome degradation in a CTSB-dependent manner.

Conclusions:

  • Inactive CDK2 protein is degraded via the autophagy-lysosome pathway.
  • The PI3Kα/AKTT308 signaling pathway plays a crucial role in regulating CDK2 degradation.
  • This study reveals a novel mechanism for CDK2 protein regulation and suggests potential therapeutic targets.
Keywords:
Autophagy–lysosomeCDK2DegradationP62/SQSTM1PI3Kα/AKT(T308)

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