Gp93 inhibits unfolded protein response-mediated c-Jun N-terminal kinase activation and cell invasion
Meng Xu1, Zhihan Wu1, Wenzhe Li1
1Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Diseases Research, School of Life Science and Technology, Tongji University, Shanghai, China.
Abstract:
In eukaryotes, Hsp90B1 serves as a vital chaperonin, facilitating the accurate folding of proteins. Interestingly, Hsp90B1 exhibits contrasting roles in the development of various types of cancers, although the underlying reasons for this duality remain enigmatic. Through the utilization of the Drosophila model, this study unveils the functional significance of Gp93, the Drosophila ortholog of Hsp90B1, which hitherto had limited reported developmental functions. Employing the Drosophila cell invasion model, we elucidated the pivotal role of Gp93 in regulating cell invasion and modulating c-Jun N-terminal kinase (JNK) activation. Furthermore, our investigation highlights the involvement of the unfolded protein response-associated IRE1/XBP1 pathway in governing Gp93 depletion-induced, JNK-dependent cell invasion. Collectively, these findings not only uncover a novel molecular function of Gp93 in Drosophila, but also underscore a significant consideration pertaining to the testing of Hsp90B1 inhibitors in cancer therapy.
Insights
This study reveals that Drosophila Gp93, a homolog of Hsp90B1, regulates cell invasion via the JNK pathway. This finding has implications for Hsp90B1 inhibitor cancer therapy.
Area of Science:
- Molecular Biology
- Cell Biology
- Developmental Biology
Background:
- Heat shock protein 90 beta 1 (Hsp90B1) is a crucial chaperonin in eukaryotes, essential for protein folding.
- Hsp90B1 displays contradictory roles in cancer development, with mechanisms largely unknown.
- The developmental functions of Gp93, the Drosophila ortholog of Hsp90B1, were previously underexplored.
Purpose of the Study:
- To investigate the functional role of Drosophila Gp93 in cellular processes.
- To elucidate the molecular mechanisms underlying Gp93's function in cell invasion.
- To explore the connection between Gp93, JNK signaling, and the unfolded protein response (UPR).
Main Methods:
- Utilized the Drosophila model system.
- Employed a Drosophila cell invasion assay.
- Investigated the role of the IRE1/XBP1 pathway in Gp93 depletion-induced effects.
Main Results:
- Gp93 plays a significant role in regulating cell invasion in Drosophila.
- Gp93 modulates the activation of c-Jun N-terminal kinase (JNK).
- Gp93 depletion-induced, JNK-dependent cell invasion is linked to the IRE1/XBP1 UPR pathway.
Conclusions:
- Uncovered a novel molecular function for Gp93 in Drosophila development and cell invasion.
- Established a link between Gp93, JNK signaling, and the UPR pathway in regulating cell invasion.
- Highlighted potential considerations for Hsp90B1 inhibitor-based cancer therapies.
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