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Published on: March 20, 2016
Bimodal expression of Sprouty2 during the cell cycle is mediated by phase-specific Ras/MAPK and c-Cbl activities
Christoph-Erik Mayer1, Barbara Haigl, Florian Jantscher
1Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria. christoph-erik.mayer@meduniwien.ac.at
Abstract:
Sprouty2 is an important inhibitor of cell proliferation and signal transduction. In this study, we found a bimodal expression of Sprouty2 protein during cell cycle progression after exit from quiescence, whereas elevated Sprouty4 expression in the G1 phase stayed high throughout the rest of the cell cycle. Induction of the mitogen-activated protein kinase via activated Ras was crucial for increased Sprouty2 expression at the G0/G1 transition. Following the first peak, accelerated proteasomal protein degradation caused a transient attenuation of Sprouty2 abundance during late G1. Since the decline in its expression was abolished by dominant negative c-Cbl and the timely restricted interaction between Sprouty2 and c-Cbl disappeared at the second peak of Sprouty2 expression, we conclude that the second phase in the cell cycle-specific expression profile of Sprouty2 is solely dependent on ubiquitination by c-Cbl. Our results suggest that Sprouty2 abundance is the result of strictly coordinated activities of Ras and c-Cbl.
Insights
Sprouty2 protein levels change during the cell cycle, influenced by Ras and c-Cbl. Its degradation is regulated by c-Cbl, impacting cell proliferation and signal transduction.
Area of Science:
- Cell Biology
- Molecular Biology
- Signal Transduction
Background:
- Sprouty2 acts as a key inhibitor of cell proliferation and signal transduction pathways.
- Understanding the regulation of Sprouty2 during the cell cycle is crucial for comprehending cell growth control.
Purpose of the Study:
- To investigate the cell cycle-specific expression profile of Sprouty2 protein.
- To elucidate the molecular mechanisms regulating Sprouty2 abundance during cell cycle progression.
Main Methods:
- Analysis of Sprouty2 protein expression during cell cycle progression after quiescence.
- Investigating the role of Ras-mediated mitogen-activated protein kinase signaling.
- Assessing the impact of proteasomal degradation and c-Cbl ubiquitination on Sprouty2 levels.
Main Results:
- Sprouty2 exhibited bimodal expression during cell cycle progression, contrasting with sustained high Sprouty4 levels in G1.
- Ras-induced mitogen-activated protein kinase signaling was essential for initial Sprouty2 upregulation at the G0/G1 transition.
- Accelerated proteasomal degradation transiently reduced Sprouty2 during late G1.
- The second Sprouty2 peak was dependent on c-Cbl ubiquitination, as blocking c-Cbl prevented the decline in Sprouty2 expression.
Conclusions:
- Sprouty2 abundance is tightly regulated by the coordinated actions of Ras and c-Cbl.
- c-Cbl-mediated ubiquitination is critical for the cell cycle-specific downregulation of Sprouty2.
- These findings provide insights into the molecular control of Sprouty2 during cell cycle progression and its role in signal transduction.
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