Cargando…
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...
Autores principales: | , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1785080265890070528 |
---|---|
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. |
format | Online Article Text |
id | pubmed-10380721 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT liuzhi kinasesuppressorofras1ksr1maintainsthetransformedphenotypeofbrafv600emutanthumanmelanomacells AT krsticaleksandar kinasesuppressorofras1ksr1maintainsthetransformedphenotypeofbrafv600emutanthumanmelanomacells AT neveashish kinasesuppressorofras1ksr1maintainsthetransformedphenotypeofbrafv600emutanthumanmelanomacells AT casaloucristina kinasesuppressorofras1ksr1maintainsthetransformedphenotypeofbrafv600emutanthumanmelanomacells AT rauchnora kinasesuppressorofras1ksr1maintainsthetransformedphenotypeofbrafv600emutanthumanmelanomacells AT wynnekieran kinasesuppressorofras1ksr1maintainsthetransformedphenotypeofbrafv600emutanthumanmelanomacells AT cassidyhilary kinasesuppressorofras1ksr1maintainsthetransformedphenotypeofbrafv600emutanthumanmelanomacells AT mccannamanda kinasesuppressorofras1ksr1maintainsthetransformedphenotypeofbrafv600emutanthumanmelanomacells AT kavanaghemma kinasesuppressorofras1ksr1maintainsthetransformedphenotypeofbrafv600emutanthumanmelanomacells AT mccannbrendan kinasesuppressorofras1ksr1maintainsthetransformedphenotypeofbrafv600emutanthumanmelanomacells AT blancoalfonso kinasesuppressorofras1ksr1maintainsthetransformedphenotypeofbrafv600emutanthumanmelanomacells AT rauchjens kinasesuppressorofras1ksr1maintainsthetransformedphenotypeofbrafv600emutanthumanmelanomacells AT kolchwalter kinasesuppressorofras1ksr1maintainsthetransformedphenotypeofbrafv600emutanthumanmelanomacells |