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Published on: March 27, 2020
Evidence That STK19 Is Not an NRAS-dependent Melanoma Driver
Marta Rodríguez-Martínez1, Thierry Boissiére1, Melvin Noe Gonzalez1
1Mechanisms of Transcription Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
Abstract:
STK19 was proposed to be a cancer driver, and recent work by Yin et al. (2019) in Cell suggested that the frequently recurring STK19 D89N substitution represents a gain-of-function change, allowing increased phosphorylation of NRAS to enhance melanocyte transformation. Here we show that the STK19 gene has been incorrectly annotated, and that the expressed protein is 110 amino acids shorter than indicated by current databases. The "cancer driving" STK19 D89N substitution is thus outside the coding region. We also fail to detect evidence of the mutation affecting STK19 expression; instead, it is a UV signature mutation, found in the promoter of other genes as well. Furthermore, STK19 is exclusively nuclear and chromatin-associated, while no evidence for it being a kinase was found. The data in this Matters Arising article raise fundamental questions about the recently proposed role for STK19 in melanoma progression via a function as an NRAS kinase, suggested by Yin et al. (2019) in Cell. See also the response by Yin et al. (2020), published in this issue.
Insights
STK19 gene annotation is incorrect, with the expressed protein being shorter than databases indicate. The proposed cancer-driving mutation is outside the coding region and is a UV signature, not a gain-of-function.
Area of Science:
- Molecular biology
- Cancer research
- Genetics
Background:
- The STK19 gene was proposed as a cancer driver.
- Yin et al. (2019) suggested STK19 D89N substitution enhances melanocyte transformation via NRAS phosphorylation.
Purpose of the Study:
- To re-evaluate the STK19 gene annotation and its proposed role in melanoma.
- To investigate the nature and functional impact of the STK19 D89N mutation.
Main Methods:
- Bioinformatic analysis of STK19 gene annotation.
- Mutation analysis to identify the origin of the STK19 D89N substitution.
- Cellular localization studies of STK19 protein.
- Biochemical assays to assess kinase activity.
Main Results:
- STK19 gene annotation is incorrect; the expressed protein is 110 amino acids shorter.
- The STK19 D89N substitution is outside the coding region and is a UV-signature mutation.
- STK19 is nuclear and chromatin-associated, with no evidence of kinase activity or NRAS phosphorylation.
- The mutation does not appear to affect STK19 expression.
Conclusions:
- The proposed gain-of-function mechanism for STK19 in melanoma progression is not supported by the data.
- Fundamental questions are raised regarding the role of STK19 in melanoma.
- Re-evaluation of STK19's function and annotation is necessary.
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