Somatic mutations in MAP3K5 attenuate its proapoptotic function in melanoma through increased binding to thioredoxin.

Abstract

Patients with advanced metastatic melanoma have poor prognosis and the genetics underlying its pathogenesis are poorly understood. High-throughput sequencing has allowed comprehensive discovery of somatic mutations in cancer samples. Here, on analysis of our whole-genome and whole-exome sequencing data of 29 melanoma samples, we identified several genes that harbor recurrent nonsynonymous mutations. These included MAP3K5 (mitogen-activated protein kinase kinase kinase-5), which in a prevalence screen of 288 melanomas was found to harbor a R256C substitution in 5 cases. All MAP3K5-mutated samples were wild type for BRAF, suggesting a mutual exclusivity for these mutations. Functional analysis of the MAP3K5 R256C mutation revealed attenuation of MKK4 (mitogen-activated protein kinase kinase 4) activation through increased binding of the inhibitory protein thioredoxin (TXN/TRX-1/Trx), resulting in increased proliferation and anchorage-independent growth of melanoma cells. This mutation represents a potential target for the design of new therapies to treat melanoma.

• Authors: Todd D Prickett, Brad Zerlanko, Jared J Gartner, Stephen C J Parker, Ken Dutton-Regester, Jimmy C Lin, Jamie K Teer, Xiaomu Wei, Jiji Jiang, Nisc Comparative Sequencing Program, Guo Chen, Michael A Davies, Jeffrey E Gershenwald, William Robinson, Steven Robinson, Nicholas K Hayward, Steven A Rosenberg, Elliott H Margulies, Yardena Samuels
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 134 Issue 2 Pg. 452-460 (Feb 2014) ISSN: 1523-1747 [Electronic] United States
• PMID: 24008424 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Small Interfering
• Thioredoxins
• MAP Kinase Kinase Kinase 5
• MAP3K5 protein, human
• MAP Kinase Kinase 4
• MAP2K4 protein, human

Topics

• Apoptosis (physiology)
• Cell Proliferation
• HEK293 Cells
• Humans
• MAP Kinase Kinase 4 (metabolism)
• MAP Kinase Kinase Kinase 5 (genetics, metabolism)
• Melanoma (genetics, metabolism, pathology)
• Models, Genetic
• Point Mutation
• Protein Binding
• RNA, Small Interfering (genetics)
• Signal Transduction (physiology)
• Skin Neoplasms (genetics, metabolism, pathology)
• Thioredoxins (metabolism)
• Tumor Cells, Cultured