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

被引:5
作者
Liu, Zhi [1 ]
Krstic, Aleksandar [1 ]
Neve, Ashish [1 ]
Casalou, Cristina [2 ]
Rauch, Nora [1 ]
Wynne, Kieran [1 ]
Cassidy, Hilary [1 ,3 ]
McCann, Amanda [4 ,5 ]
Kavanagh, Emma [4 ]
McCann, Brendan [1 ]
Blanco, Alfonso [5 ]
Rauch, Jens [1 ,3 ]
Kolch, Walter [1 ,4 ]
机构
[1] Univ Coll Dublin, Sch Med, Syst Biol Ireland SBI, Dublin D04 V1W8, Ireland
[2] Univ Coll Dublin, Charles Inst Dermatol, Sch Med, Dublin D04 V1W8, Ireland
[3] Univ Coll Dublin, Sch Biomol & Biomed Sci, Dublin D04 V1W8, Ireland
[4] Univ Coll Dublin, Sch Med, Dublin D04 V1W8, Ireland
[5] Univ Coll Dublin, Conway Inst, Dublin D04 V1W8, Ireland
基金
爱尔兰科学基金会;
关键词
melanoma; KSR1; apoptosis; senescence; proliferation; ACTIVATED PROTEIN-KINASE; COMPREHENSIVE ANALYSIS; INDUCED APOPTOSIS; SENESCENCE; P38; CAVEOLIN-1;
D O I
10.3390/ijms241411821
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页数:16
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