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Published on: October 5, 2020
Dynamic regulation of RAS and RAS signaling
Walter Kolch1,2, Dénes Berta3, Edina Rosta3
1Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
Abstract:
RAS proteins regulate most aspects of cellular physiology. They are mutated in 30% of human cancers and 4% of developmental disorders termed Rasopathies. They cycle between active GTP-bound and inactive GDP-bound states. When active, they can interact with a wide range of effectors that control fundamental biochemical and biological processes. Emerging evidence suggests that RAS proteins are not simple on/off switches but sophisticated information processing devices that compute cell fate decisions by integrating external and internal cues. A critical component of this compute function is the dynamic regulation of RAS activation and downstream signaling that allows RAS to produce a rich and nuanced spectrum of biological outputs. We discuss recent findings how the dynamics of RAS and its downstream signaling is regulated. Starting from the structural and biochemical properties of wild-type and mutant RAS proteins and their activation cycle, we examine higher molecular assemblies, effector interactions and downstream signaling outputs, all under the aspect of dynamic regulation. We also consider how computational and mathematical modeling approaches contribute to analyze and understand the pleiotropic functions of RAS in health and disease.
Insights
RAS proteins are key regulators of cell function, acting as sophisticated information processors involved in cancer and developmental disorders. Their dynamic regulation controls cell fate by integrating signals, impacting diverse biological processes.
Area of Science:
- Molecular Biology
- Cellular Physiology
- Biochemistry
Background:
- RAS proteins are crucial regulators of cellular physiology, implicated in 30% of human cancers and 4% of Rasopathies.
- They cycle between active (GTP-bound) and inactive (GDP-bound) states, interacting with effectors to control biological processes.
Purpose of the Study:
- To explore the dynamic regulation of RAS activation and downstream signaling.
- To understand RAS proteins as information processing devices that compute cell fate decisions.
Main Methods:
- Review of structural and biochemical properties of RAS proteins.
- Examination of higher molecular assemblies and effector interactions.
- Analysis of computational and mathematical modeling approaches.
Main Results:
- RAS proteins function as sophisticated information processing devices, not simple on/off switches.
- Dynamic regulation of RAS activation and signaling produces a nuanced spectrum of biological outputs.
- Computational modeling aids in understanding RAS functions in health and disease.
Conclusions:
- The dynamic regulation of RAS signaling is critical for its complex cellular functions.
- Understanding RAS dynamics offers insights into cancer and developmental disorders.
- Integrated approaches, including modeling, are essential for deciphering RAS pleiotropic functions.
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