title: 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.affiliation: The Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Prickett
authors.affiliation: The Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Zerlanko
authors.affiliation: The Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Gartner
authors.affiliation: The Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Stephen C J
authors.initials: SCJ
authors.lastname: Parker
authors.affiliation: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.
authors.forename: Ken
authors.initials: K
authors.lastname: Dutton-Regester
authors.affiliation: Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA.
authors.forename: Jimmy C
authors.initials: JC
authors.lastname: Lin
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Teer
authors.affiliation: The Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Xiaomu
authors.initials: X
authors.lastname: Wei
authors.affiliation: The Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jiji
authors.initials: J
authors.lastname: Jiang
authors.affiliation: NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.lastname: Nisc Comparative Sequencing Program
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Gershenwald
authors.affiliation: Division of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: William
authors.initials: W
authors.lastname: Robinson
authors.affiliation: Division of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Robinson
authors.affiliation: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.affiliation: The Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.affiliation: Genome Informatics Section, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Elliott H
authors.initials: EH
authors.lastname: Margulies
authors.affiliation: The Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. Electronic address: Yardena.samuels@weizmann.ac.il.
authors.forename: Yardena
authors.initials: Y
authors.lastname: Samuels
mesh_terms: D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D057809:HEK293 Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics* / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008957:Models, Genetic; D017354:Point Mutation; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D013879:Thioredoxins / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D034741:RNA, Small Interfering; D013879:Thioredoxins; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human