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E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression

Transforming growth factor β (TGFβ) is a secreted growth and differentiation factor that influences vital cellular processes like proliferation, adhesion, motility, and apoptosis. Regulation of the TGFβ signaling pathway is of key importance to maintain tissue homeostasis. Perturbation of this signa...

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Autores principales: Sinha, Abhishek, Iyengar, Prasanna Vasudevan, ten Dijke, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825147/
https://www.ncbi.nlm.nih.gov/pubmed/33418880
http://dx.doi.org/10.3390/ijms22020476
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author Sinha, Abhishek
Iyengar, Prasanna Vasudevan
ten Dijke, Peter
author_facet Sinha, Abhishek
Iyengar, Prasanna Vasudevan
ten Dijke, Peter
author_sort Sinha, Abhishek
collection PubMed
description Transforming growth factor β (TGFβ) is a secreted growth and differentiation factor that influences vital cellular processes like proliferation, adhesion, motility, and apoptosis. Regulation of the TGFβ signaling pathway is of key importance to maintain tissue homeostasis. Perturbation of this signaling pathway has been implicated in a plethora of diseases, including cancer. The effect of TGFβ is dependent on cellular context, and TGFβ can perform both anti- and pro-oncogenic roles. TGFβ acts by binding to specific cell surface TGFβ type I and type II transmembrane receptors that are endowed with serine/threonine kinase activity. Upon ligand-induced receptor phosphorylation, SMAD proteins and other intracellular effectors become activated and mediate biological responses. The levels, localization, and function of TGFβ signaling mediators, regulators, and effectors are highly dynamic and regulated by a myriad of post-translational modifications. One such crucial modification is ubiquitination. The ubiquitin modification is also a mechanism by which crosstalk with other signaling pathways is achieved. Crucial effector components of the ubiquitination cascade include the very diverse family of E3 ubiquitin ligases. This review summarizes the diverse roles of E3 ligases that act on TGFβ receptor and intracellular signaling components. E3 ligases regulate TGFβ signaling both positively and negatively by regulating degradation of receptors and various signaling intermediates. We also highlight the function of E3 ligases in connection with TGFβ’s dual role during tumorigenesis. We conclude with a perspective on the emerging possibility of defining E3 ligases as drug targets and how they may be used to selectively target TGFβ-induced pro-oncogenic responses.
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spelling pubmed-78251472021-01-24 E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression Sinha, Abhishek Iyengar, Prasanna Vasudevan ten Dijke, Peter Int J Mol Sci Review Transforming growth factor β (TGFβ) is a secreted growth and differentiation factor that influences vital cellular processes like proliferation, adhesion, motility, and apoptosis. Regulation of the TGFβ signaling pathway is of key importance to maintain tissue homeostasis. Perturbation of this signaling pathway has been implicated in a plethora of diseases, including cancer. The effect of TGFβ is dependent on cellular context, and TGFβ can perform both anti- and pro-oncogenic roles. TGFβ acts by binding to specific cell surface TGFβ type I and type II transmembrane receptors that are endowed with serine/threonine kinase activity. Upon ligand-induced receptor phosphorylation, SMAD proteins and other intracellular effectors become activated and mediate biological responses. The levels, localization, and function of TGFβ signaling mediators, regulators, and effectors are highly dynamic and regulated by a myriad of post-translational modifications. One such crucial modification is ubiquitination. The ubiquitin modification is also a mechanism by which crosstalk with other signaling pathways is achieved. Crucial effector components of the ubiquitination cascade include the very diverse family of E3 ubiquitin ligases. This review summarizes the diverse roles of E3 ligases that act on TGFβ receptor and intracellular signaling components. E3 ligases regulate TGFβ signaling both positively and negatively by regulating degradation of receptors and various signaling intermediates. We also highlight the function of E3 ligases in connection with TGFβ’s dual role during tumorigenesis. We conclude with a perspective on the emerging possibility of defining E3 ligases as drug targets and how they may be used to selectively target TGFβ-induced pro-oncogenic responses. MDPI 2021-01-06 /pmc/articles/PMC7825147/ /pubmed/33418880 http://dx.doi.org/10.3390/ijms22020476 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Sinha, Abhishek
Iyengar, Prasanna Vasudevan
ten Dijke, Peter
E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression
title E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression
title_full E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression
title_fullStr E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression
title_full_unstemmed E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression
title_short E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression
title_sort e3 ubiquitin ligases: key regulators of tgfβ signaling in cancer progression
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825147/
https://www.ncbi.nlm.nih.gov/pubmed/33418880
http://dx.doi.org/10.3390/ijms22020476
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