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Scaffold coupling: ERK activation by trans-phosphorylation across different scaffold protein species
RAS-ERK (extracellular signal–regulated kinase) pathway signals are modulated by scaffold proteins that assemble the components of different kinase tiers into a sequential phosphorylation cascade. In the prevailing model scaffold proteins function as isolated entities, where the flux of phosphorylat...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9931222/ https://www.ncbi.nlm.nih.gov/pubmed/36791195 http://dx.doi.org/10.1126/sciadv.add7969 |
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author | Martín-Vega, Ana Ruiz-Peinado, Laura García-Gómez, Rocío Herrero, Ana de la Fuente-Vivas, Dalia Parvathaneni, Swetha Caloto, Rubén Morante, Marta von Kriegsheim, Alex Bustelo, Xosé R. Sacks, David B. Casar, Berta Crespo, Piero |
author_facet | Martín-Vega, Ana Ruiz-Peinado, Laura García-Gómez, Rocío Herrero, Ana de la Fuente-Vivas, Dalia Parvathaneni, Swetha Caloto, Rubén Morante, Marta von Kriegsheim, Alex Bustelo, Xosé R. Sacks, David B. Casar, Berta Crespo, Piero |
author_sort | Martín-Vega, Ana |
collection | PubMed |
description | RAS-ERK (extracellular signal–regulated kinase) pathway signals are modulated by scaffold proteins that assemble the components of different kinase tiers into a sequential phosphorylation cascade. In the prevailing model scaffold proteins function as isolated entities, where the flux of phosphorylation events progresses downstream linearly, to achieve ERK phosphorylation. We show that different types of scaffold proteins, specifically KSR1 (kinase suppressor of Ras 1) and IQGAP1 (IQ motif-containing guanosine triphosphatase activating protein 1), can bind to each other, forming a complex whereby phosphorylation reactions occur across both species. MEK (mitogen-activated protein kinase kinase) bound to IQGAP1 can phosphorylate ERK docked at KSR1, a process that we have named “trans-phosphorylation.” We also reveal that ERK trans-phosphorylation participates in KSR1-regulated adipogenesis, and it also underlies the modest cytotoxicity exhibited by KSR-directed inhibitors. Overall, we identify interactions between scaffold proteins and trans-phosphorylation as an additional level of regulation in the ERK cascade, with broad implications in signaling and the design of scaffold protein–aimed therapeutics. |
format | Online Article Text |
id | pubmed-9931222 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-99312222023-02-16 Scaffold coupling: ERK activation by trans-phosphorylation across different scaffold protein species Martín-Vega, Ana Ruiz-Peinado, Laura García-Gómez, Rocío Herrero, Ana de la Fuente-Vivas, Dalia Parvathaneni, Swetha Caloto, Rubén Morante, Marta von Kriegsheim, Alex Bustelo, Xosé R. Sacks, David B. Casar, Berta Crespo, Piero Sci Adv Biomedicine and Life Sciences RAS-ERK (extracellular signal–regulated kinase) pathway signals are modulated by scaffold proteins that assemble the components of different kinase tiers into a sequential phosphorylation cascade. In the prevailing model scaffold proteins function as isolated entities, where the flux of phosphorylation events progresses downstream linearly, to achieve ERK phosphorylation. We show that different types of scaffold proteins, specifically KSR1 (kinase suppressor of Ras 1) and IQGAP1 (IQ motif-containing guanosine triphosphatase activating protein 1), can bind to each other, forming a complex whereby phosphorylation reactions occur across both species. MEK (mitogen-activated protein kinase kinase) bound to IQGAP1 can phosphorylate ERK docked at KSR1, a process that we have named “trans-phosphorylation.” We also reveal that ERK trans-phosphorylation participates in KSR1-regulated adipogenesis, and it also underlies the modest cytotoxicity exhibited by KSR-directed inhibitors. Overall, we identify interactions between scaffold proteins and trans-phosphorylation as an additional level of regulation in the ERK cascade, with broad implications in signaling and the design of scaffold protein–aimed therapeutics. American Association for the Advancement of Science 2023-02-15 /pmc/articles/PMC9931222/ /pubmed/36791195 http://dx.doi.org/10.1126/sciadv.add7969 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Martín-Vega, Ana Ruiz-Peinado, Laura García-Gómez, Rocío Herrero, Ana de la Fuente-Vivas, Dalia Parvathaneni, Swetha Caloto, Rubén Morante, Marta von Kriegsheim, Alex Bustelo, Xosé R. Sacks, David B. Casar, Berta Crespo, Piero Scaffold coupling: ERK activation by trans-phosphorylation across different scaffold protein species |
title | Scaffold coupling: ERK activation by trans-phosphorylation across different scaffold protein species |
title_full | Scaffold coupling: ERK activation by trans-phosphorylation across different scaffold protein species |
title_fullStr | Scaffold coupling: ERK activation by trans-phosphorylation across different scaffold protein species |
title_full_unstemmed | Scaffold coupling: ERK activation by trans-phosphorylation across different scaffold protein species |
title_short | Scaffold coupling: ERK activation by trans-phosphorylation across different scaffold protein species |
title_sort | scaffold coupling: erk activation by trans-phosphorylation across different scaffold protein species |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9931222/ https://www.ncbi.nlm.nih.gov/pubmed/36791195 http://dx.doi.org/10.1126/sciadv.add7969 |
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