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Kinase Suppressor of RAS 1 (KSR1) Maintains the Transformed Phenotype of BRAFV600E Mutant Human Melanoma Cells

Kinase Suppressor of RAS 1 (KSR1) is a scaffolding protein for the RAS-RAF-MEK-ERK pathway, which is one of the most frequently altered pathways in human cancers. Previous results have shown that KSR1 has a critical role in mutant RAS-mediated transformation. Here, we examined the role of KSR1 in mu...

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Autores principales: Liu, Zhi, Krstic, Aleksandar, Neve, Ashish, Casalou, Cristina, Rauch, Nora, Wynne, Kieran, Cassidy, Hilary, McCann, Amanda, Kavanagh, Emma, McCann, Brendan, Blanco, Alfonso, Rauch, Jens, Kolch, Walter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10380721/
https://www.ncbi.nlm.nih.gov/pubmed/37511580
http://dx.doi.org/10.3390/ijms241411821
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author Liu, Zhi
Krstic, Aleksandar
Neve, Ashish
Casalou, Cristina
Rauch, Nora
Wynne, Kieran
Cassidy, Hilary
McCann, Amanda
Kavanagh, Emma
McCann, Brendan
Blanco, Alfonso
Rauch, Jens
Kolch, Walter
author_facet Liu, Zhi
Krstic, Aleksandar
Neve, Ashish
Casalou, Cristina
Rauch, Nora
Wynne, Kieran
Cassidy, Hilary
McCann, Amanda
Kavanagh, Emma
McCann, Brendan
Blanco, Alfonso
Rauch, Jens
Kolch, Walter
author_sort Liu, Zhi
collection PubMed
description Kinase Suppressor of RAS 1 (KSR1) is a scaffolding protein for the RAS-RAF-MEK-ERK pathway, which is one of the most frequently altered pathways in human cancers. Previous results have shown that KSR1 has a critical role in mutant RAS-mediated transformation. Here, we examined the role of KSR1 in mutant BRAF transformation. We used CRISPR/Cas9 to knock out KSR1 in a BRAFV600E-transformed melanoma cell line. KSR1 loss produced a complex phenotype characterised by impaired proliferation, cell cycle defects, decreased transformation, decreased invasive migration, increased cellular senescence, and increased apoptosis. To decipher this phenotype, we used a combination of proteomic ERK substrate profiling, global protein expression profiling, and biochemical validation assays. The results suggest that KSR1 directs ERK to phosphorylate substrates that have a critical role in ensuring cell survival. The results further indicate that KSR1 loss induces the activation of p38 Mitogen-Activated Protein Kinase (MAPK) and subsequent cell cycle aberrations and senescence. In summary, KSR1 function plays a key role in oncogenic BRAF transformation.
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spelling pubmed-103807212023-07-29 Kinase Suppressor of RAS 1 (KSR1) Maintains the Transformed Phenotype of BRAFV600E Mutant Human Melanoma Cells Liu, Zhi Krstic, Aleksandar Neve, Ashish Casalou, Cristina Rauch, Nora Wynne, Kieran Cassidy, Hilary McCann, Amanda Kavanagh, Emma McCann, Brendan Blanco, Alfonso Rauch, Jens Kolch, Walter Int J Mol Sci Article Kinase Suppressor of RAS 1 (KSR1) is a scaffolding protein for the RAS-RAF-MEK-ERK pathway, which is one of the most frequently altered pathways in human cancers. Previous results have shown that KSR1 has a critical role in mutant RAS-mediated transformation. Here, we examined the role of KSR1 in mutant BRAF transformation. We used CRISPR/Cas9 to knock out KSR1 in a BRAFV600E-transformed melanoma cell line. KSR1 loss produced a complex phenotype characterised by impaired proliferation, cell cycle defects, decreased transformation, decreased invasive migration, increased cellular senescence, and increased apoptosis. To decipher this phenotype, we used a combination of proteomic ERK substrate profiling, global protein expression profiling, and biochemical validation assays. The results suggest that KSR1 directs ERK to phosphorylate substrates that have a critical role in ensuring cell survival. The results further indicate that KSR1 loss induces the activation of p38 Mitogen-Activated Protein Kinase (MAPK) and subsequent cell cycle aberrations and senescence. In summary, KSR1 function plays a key role in oncogenic BRAF transformation. MDPI 2023-07-23 /pmc/articles/PMC10380721/ /pubmed/37511580 http://dx.doi.org/10.3390/ijms241411821 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Liu, Zhi
Krstic, Aleksandar
Neve, Ashish
Casalou, Cristina
Rauch, Nora
Wynne, Kieran
Cassidy, Hilary
McCann, Amanda
Kavanagh, Emma
McCann, Brendan
Blanco, Alfonso
Rauch, Jens
Kolch, Walter
Kinase Suppressor of RAS 1 (KSR1) Maintains the Transformed Phenotype of BRAFV600E Mutant Human Melanoma Cells
title Kinase Suppressor of RAS 1 (KSR1) Maintains the Transformed Phenotype of BRAFV600E Mutant Human Melanoma Cells
title_full Kinase Suppressor of RAS 1 (KSR1) Maintains the Transformed Phenotype of BRAFV600E Mutant Human Melanoma Cells
title_fullStr Kinase Suppressor of RAS 1 (KSR1) Maintains the Transformed Phenotype of BRAFV600E Mutant Human Melanoma Cells
title_full_unstemmed Kinase Suppressor of RAS 1 (KSR1) Maintains the Transformed Phenotype of BRAFV600E Mutant Human Melanoma Cells
title_short Kinase Suppressor of RAS 1 (KSR1) Maintains the Transformed Phenotype of BRAFV600E Mutant Human Melanoma Cells
title_sort kinase suppressor of ras 1 (ksr1) maintains the transformed phenotype of brafv600e mutant human melanoma cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10380721/
https://www.ncbi.nlm.nih.gov/pubmed/37511580
http://dx.doi.org/10.3390/ijms241411821
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