JNK inhibition arrests cotranslational degradation

Area of Science:

• Cell Biology
• Molecular Biology

Background:

• Fibronectin adhesion activates beta(1)-integrin, initiating a PI3K cascade that influences eukaryotic initiation factor 4F (eIF4F) complex formation.
• This process stimulates protein synthesis (translation) in fibroblasts.

Purpose of the Study:

• To investigate the specific kinases within the PI3K cascade responsible for fibronectin-stimulated translation.
• To elucidate the relationship between protein synthesis and degradation pathways.

Main Methods:

• Utilized pharmacological inhibitors of kinases, including SP600125 (JNK inhibitor) and MG132 (proteasome inhibitor).
• Measured (35)S-methionine incorporation to assess protein synthesis.
• Analyzed translation initiation and protein degradation mechanisms.

Main Results:

• JNK inhibition increased methionine incorporation but reduced translation initiation, indicating concurrent protein degradation.
• Proteasome inhibition also enhanced methionine incorporation, confirming the role of degradation.
• Cotranslational degradation was dependent on PI3K activation, while serum promoted translation independently of degradation.
• JNK inhibition led to eIF2alpha phosphorylation, potentially explaining reduced translation initiation.

Conclusions:

• Beta(1)-integrin-mediated translation stimulates the synthesis of short-lived proteins.
• The c-Jun N-terminal kinase (JNK) pathway controls the degradation of these proteins.
• JNK is hypothesized to be a general regulator of cotranslational degradation.