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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.<\/jats:p>","DOI":"10.3390\/ijms241411821","type":"journal-article","created":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T00:47:03Z","timestamp":1690159623000},"page":"11821","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Kinase Suppressor of RAS 1 (KSR1) Maintains the Transformed Phenotype of BRAFV600E Mutant Human Melanoma Cells"],"prefix":"10.3390","volume":"24","author":[{"given":"Zhi","family":"Liu","sequence":"first","affiliation":[{"name":"Systems Biology Ireland (SBI), School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}]},{"given":"Aleksandar","family":"Krstic","sequence":"additional","affiliation":[{"name":"Systems Biology Ireland (SBI), School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5076-8355","authenticated-orcid":false,"given":"Ashish","family":"Neve","sequence":"additional","affiliation":[{"name":"Systems Biology Ireland (SBI), School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3198-2783","authenticated-orcid":false,"given":"Cristina","family":"Casalou","sequence":"additional","affiliation":[{"name":"Charles Institute of Dermatology, School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}]},{"given":"Nora","family":"Rauch","sequence":"additional","affiliation":[{"name":"Systems Biology Ireland (SBI), School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}]},{"given":"Kieran","family":"Wynne","sequence":"additional","affiliation":[{"name":"Systems Biology Ireland (SBI), School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}]},{"given":"Hilary","family":"Cassidy","sequence":"additional","affiliation":[{"name":"Systems Biology Ireland (SBI), School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"},{"name":"School of Biomolecular & Biomedical Science, University College Dublin, D04 V1W8 Dublin, Ireland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1911-3307","authenticated-orcid":false,"given":"Amanda","family":"McCann","sequence":"additional","affiliation":[{"name":"School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"},{"name":"Conway Institute, University College Dublin, D04 V1W8 Dublin, Ireland"}]},{"given":"Emma","family":"Kavanagh","sequence":"additional","affiliation":[{"name":"School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}]},{"given":"Brendan","family":"McCann","sequence":"additional","affiliation":[{"name":"Systems Biology Ireland (SBI), School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}]},{"given":"Alfonso","family":"Blanco","sequence":"additional","affiliation":[{"name":"Conway Institute, University College Dublin, D04 V1W8 Dublin, Ireland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5120-9547","authenticated-orcid":false,"given":"Jens","family":"Rauch","sequence":"additional","affiliation":[{"name":"Systems Biology Ireland (SBI), School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"},{"name":"School of Biomolecular & Biomedical Science, University College Dublin, D04 V1W8 Dublin, Ireland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5777-5016","authenticated-orcid":false,"given":"Walter","family":"Kolch","sequence":"additional","affiliation":[{"name":"Systems Biology Ireland (SBI), School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"},{"name":"School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lee, S., Rauch, J., and Kolch, W. 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