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

Abstract

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.

• Authors: Zhi Liu, Aleksandar Krstic, Ashish Neve, Cristina Casalou, Nora Rauch, Kieran Wynne, Hilary Cassidy, Amanda McCann, Emma Kavanagh, Brendan McCann, Alfonso Blanco, Jens Rauch, Walter Kolch
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 14 (Jul 23 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 37511580 (Publication Type: Journal Article)

Chemical References

• KSR-1 protein kinase
• Proto-Oncogene Proteins B-raf
• ras Proteins
• BRAF protein, human

Topics

• Humans
• MAP Kinase Signaling System
• Melanoma (genetics)
• Proteomics
• Proto-Oncogene Proteins B-raf (genetics, metabolism)
• ras Proteins (metabolism)