Somatic Mutations in MAP3K5 Attenuate Its Proapoptotic Function in Melanoma through Increased Binding to Thioredoxin

• DOI: 10.1038/jid.2013.365
• Publication Date: 2013-09-05T14:09:34Z
• 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...; Guo Chen; Michael A. Davies; Jeffrey E. Gershe...; William Robinson; Steven Robinson; Nicholas K. Hayward; Steven A. Rosenberg; Elliott H. Margulies; Yardena Samuels
• Keywords: Nonsynonymous substitution; c-Raf

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.