Abstract |
Activating mutations in NRAS account for 20%-30% of melanoma, but despite decades of research and in contrast to BRAF, no effective anti-NRAS therapies have been forthcoming. Here, we identify a previously uncharacterized serine/threonine kinase STK19 as a novel NRAS activator. STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation. A recurrent D89N substitution in STK19 whose alterations were identified in 25% of human melanomas represents a gain-of-function mutation that interacts better with NRAS to enhance melanocyte transformation. STK19D89N knockin leads to skin hyperpigmentation and promotes NRASQ61R-driven melanomagenesis in vivo. Finally, we developed ZT-12-037-01 (1a) as a specific STK19-targeted inhibitor and showed that it effectively blocks oncogenic NRAS-driven melanocyte malignant transformation and melanoma growth in vitro and in vivo. Together, our findings provide a new and viable therapeutic strategy for melanomas harboring NRAS mutations.
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Authors | Chengqian Yin, Bo Zhu, Ting Zhang, Tongzheng Liu, Shuyang Chen, Yu Liu, Xin Li, Xiao Miao, Shanshan Li, Xia Mi, Jie Zhang, Li Li, Guo Wei, Zhi-Xiang Xu, Xiumei Gao, Canhua Huang, Zhi Wei, Colin R Goding, Peng Wang, Xianming Deng, Rutao Cui |
Journal | Cell
(Cell)
Vol. 176
Issue 5
Pg. 1113-1127.e16
(02 21 2019)
ISSN: 1097-4172 [Electronic] United States |
PMID | 30712867
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2019 Elsevier Inc. All rights reserved. |
Chemical References |
- Membrane Proteins
- Nuclear Proteins
- Protein Serine-Threonine Kinases
- Proto-Oncogene Proteins B-raf
- STK19 protein, human
- GTP Phosphohydrolases
- NRAS protein, human
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Topics |
- Animals
- Cell Line, Tumor
- Cell Transformation, Neoplastic
- Female
- GTP Phosphohydrolases
(metabolism)
- HEK293 Cells
- Humans
- Melanocytes
(metabolism)
- Melanoma
(genetics, metabolism)
- Membrane Proteins
(metabolism)
- Mice
- Mice, Inbred C57BL
- Mice, Nude
- Mutation
- Nuclear Proteins
(metabolism)
- Phosphorylation
- Protein Serine-Threonine Kinases
(metabolism)
- Proto-Oncogene Proteins B-raf
(metabolism)
- Signal Transduction
- Skin Neoplasms
(genetics)
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