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Updated: Jul 21, 2025

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
06:09

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

Zhi Liu1, Aleksandar Krstic1, Ashish Neve1

  • 1Systems Biology Ireland (SBI), School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland.

International Journal of Molecular Sciences
|July 29, 2023
PubMed

Insights

Kinase Suppressor of RAS 1 (KSR1) is crucial for BRAF-driven cancer growth. Its absence impairs cell proliferation and promotes senescence, revealing KSR1

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • The RAS-RAF-MEK-ERK pathway is frequently altered in human cancers.
  • Kinase Suppressor of RAS 1 (KSR1) is a scaffolding protein within this pathway.
  • KSR1 is known to be critical for mutant RAS-mediated transformation.

Purpose of the Study:

  • To investigate the role of KSR1 in BRAFV600E-driven melanoma transformation.
  • To elucidate the molecular mechanisms underlying KSR1's function in oncogenic transformation.

Main Methods:

  • CRISPR/Cas9 gene editing to knock out KSR1 in a BRAFV600E melanoma cell line.
  • Proteomic ERK substrate profiling.
  • Global protein expression profiling and biochemical validation assays.

Main Results:

  • KSR1 loss resulted in impaired proliferation, cell cycle defects, reduced transformation, and decreased migration.
  • KSR1 deficiency led to increased cellular senescence and apoptosis.
  • KSR1 directs ERK phosphorylation of substrates vital for cell survival and its loss activates p38 MAPK, causing cell cycle aberrations and senescence.

Conclusions:

  • KSR1 plays a significant role in supporting oncogenic BRAF transformation.
  • KSR1 is essential for maintaining cell survival and proliferation in BRAFV600E-transformed cells.
  • Targeting KSR1 may represent a therapeutic strategy for BRAF-mutant cancers.
Keywords:
KSR1apoptosismelanomaproliferationsenescence

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