Dataset Information

(Full Proteome) Kinase Suppressor of RAS 1 (KSR1) maintains the transformed phenotype of BRAFV600E mutant human melanoma cells

ABSTRACT: 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 characterized 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 furtherindicate 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.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Melanocyte, Cell Culture

DISEASE(S): Melanoma

SUBMITTER: Kieran Wynne

LAB HEAD: Walter Kolch

PROVIDER: PXD036265 | Pride | 2023-08-15

REPOSITORIES: Pride

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Publications

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

Liu Zhi Z Krstic Aleksandar A Neve Ashish A Casalou Cristina C Rauch Nora N Wynne Kieran K Cassidy Hilary H McCann Amanda A Kavanagh Emma E McCann Brendan B Blanco Alfonso A Rauch Jens J Kolch Walter W

International journal of molecular sciences 20230723 14

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 cycl ...[more]

PMID: 37511580

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Project description:Padala2017- ERK, PI3K/Akt and Wnt signalling network (bRaf mutated) Crosstalk model of the ERK, Wnt and Akt signalling pathways with bRaf mutation This model is described in the article: Cancerous perturbations within the ERK, PI3K/Akt, and Wnt/?-catenin signaling network constitutively activate inter-pathway positive feedback loops. Padala RR, Karnawat R, Viswanathan SB, Thakkar AV, Das AB. Mol Biosyst 2017 May; 13(5): 830-840 Abstract: Perturbations in molecular signaling pathways are a result of genetic or epigenetic alterations, which may lead to malignant transformation of cells. Despite cellular robustness, specific genetic or epigenetic changes of any gene can trigger a cascade of failures, which result in the malfunctioning of cell signaling pathways and lead to cancer phenotypes. The extent of cellular robustness has a link with the architecture of the network such as feedback and feedforward loops. Perturbation in components within feedback loops causes a transition from a regulated to a persistently activated state and results in uncontrolled cell growth. This work represents the mathematical and quantitative modeling of ERK, PI3K/Akt, and Wnt/?-catenin signaling crosstalk to show the dynamics of signaling responses during genetic and epigenetic changes in cancer. ERK, PI3K/Akt, and Wnt/?-catenin signaling crosstalk networks include both intra and inter-pathway feedback loops which function in a controlled fashion in a healthy cell. Our results show that cancerous perturbations of components such as EGFR, Ras, B-Raf, PTEN, and components of the destruction complex cause extreme fragility in the network and constitutively activate inter-pathway positive feedback loops. We observed that the aberrant signaling response due to the failure of specific network components is transmitted throughout the network via crosstalk, generating an additive effect on cancer growth and proliferation. This model is hosted on BioModels Database and identified by: BIOMD0000000653. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

(Full Proteome) Kinase Suppressor of RAS 1 (KSR1) maintains the transformed phenotype of BRAFV600E mutant human melanoma cells

Publications

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

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