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Review ArticleReview Article

Regulation of Mitogen-Activated Protein Kinase Signaling Pathways by the Ubiquitin-Proteasome System and Its Pharmacological Potential

Simon Mathien, Chloé Tesnière and Sylvain Meloche
Michael Gottesman, ASSOCIATE EDITOR
Pharmacological Reviews October 2021, 73 (4) 1434-1467; DOI: https://doi.org/10.1124/pharmrev.120.000170
Simon Mathien
Institute for Research in Immunology and Cancer, Montreal, Quebec, Canada (S.Ma., C.T., S.Me.); and Molecular Biology Program, Faculty of Medicine (C.T., S.Me.) and Department of Pharmacology and Physiology (S.Me.), Université de Montréal, Montreal, Quebec, Canada
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Chloé Tesnière
Institute for Research in Immunology and Cancer, Montreal, Quebec, Canada (S.Ma., C.T., S.Me.); and Molecular Biology Program, Faculty of Medicine (C.T., S.Me.) and Department of Pharmacology and Physiology (S.Me.), Université de Montréal, Montreal, Quebec, Canada
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Sylvain Meloche
Institute for Research in Immunology and Cancer, Montreal, Quebec, Canada (S.Ma., C.T., S.Me.); and Molecular Biology Program, Faculty of Medicine (C.T., S.Me.) and Department of Pharmacology and Physiology (S.Me.), Université de Montréal, Montreal, Quebec, Canada
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Michael Gottesman
Roles: ASSOCIATE EDITOR
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Abstract

Mitogen-activated protein kinase (MAPK) cascades are evolutionarily conserved signaling pathways that play essential roles in transducing extracellular environmental signals into diverse cellular responses to maintain homeostasis. These pathways are classically organized into an architecture of three sequentially acting protein kinases: a MAPK kinase kinase that phosphorylates and activates a MAPK kinase, which in turn phosphorylates and activates the effector MAPK. The activity of MAPKs is tightly regulated by phosphorylation of their activation loop, which can be modulated by positive and negative feedback mechanisms to control the amplitude and duration of the signal. The signaling outcomes of MAPK pathways are further regulated by interactions of MAPKs with scaffolding and regulatory proteins. Accumulating evidence indicates that, in addition to these mechanisms, MAPK signaling is commonly regulated by ubiquitin-proteasome system (UPS)-mediated control of the stability and abundance of MAPK pathway components. Notably, the biologic activity of some MAPKs appears to be regulated mainly at the level of protein turnover. Recent studies have started to explore the potential of targeted protein degradation as a powerful strategy to investigate the biologic functions of individual MAPK pathway components and as a new therapeutic approach to overcome resistance to current small-molecule kinase inhibitors. Here, we comprehensively review the mechanisms, physiologic importance, and pharmacological potential of UPS-mediated protein degradation in the control of MAPK signaling.

Significance Statement Accumulating evidence highlights the importance of targeted protein degradation by the ubiquitin-proteasome system in regulating and fine-tuning the signaling output of mitogen-activated protein kinase (MAPK) pathways. Manipulating protein levels of MAPK cascade components may provide a novel approach for the development of selective pharmacological tools and therapeutics.

Footnotes

  • Work in the Meloche laboratory was supported by grants from the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, and the Cancer Research Society.

  • The authors declare that they have no conflict of interest with the contents of this article.

  • An earlier version of this paper appears in Regulation of MAP Kinase Signaling Pathways by the Ubiquitin-Proteasome System and Pharmacological Potential under the doi PHARMREV-PS-2020-000170.

  • https://doi.org/10.1124/pharmrev.120.000170.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 73 (4)
Pharmacological Reviews
Vol. 73, Issue 4
1 Oct 2021
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Review ArticleReview Article

Regulation of MAPK Stability

Simon Mathien, Chloé Tesnière and Sylvain Meloche
Pharmacological Reviews October 1, 2021, 73 (4) 1434-1467; DOI: https://doi.org/10.1124/pharmrev.120.000170

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Review ArticleReview Article

Regulation of MAPK Stability

Simon Mathien, Chloé Tesnière and Sylvain Meloche
Pharmacological Reviews October 1, 2021, 73 (4) 1434-1467; DOI: https://doi.org/10.1124/pharmrev.120.000170
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  • Article
    • Visual Overview
    • Abstract
    • I. Introduction
    • II. Classic Mitogen-Activated Protein Kinase Pathways
    • III. Atypical Mitogen-Activated Protein Kinase Pathways
    • IV. Targeting Mitogen-Activated Protein Kinase Stability as a New Pharmacological Strategy
    • V. Concluding Remarks
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