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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Bibliographic Details
Published in:International journal of molecular sciences 2023-07, Vol.24 (14), p.11821
Main Authors: 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
Format: Article
Language:English
Subjects:
Apoptosis
Biotechnology industry
Cancer
Cell cycle
Cell growth
Cloning
Genetic aspects
Genotype & phenotype
Humans
Kinases
MAP Kinase Signaling System
Melanoma
Melanoma - genetics
Phosphorylation
Protein expression
Protein kinases
Proteins
Proteomics
Proto-Oncogene Proteins B-raf - genetics
Proto-Oncogene Proteins B-raf - metabolism
ras Proteins - metabolism
Scientific equipment and supplies industry
Senescence
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms241411821