title: Somatic mutation of GRIN2A in malignant melanoma results in loss of tumor suppressor activity via aberrant NMDAR complex formation.
abstract: The ionotropic glutamate receptors (N-methyl-D-aspartate receptors (NMDARs)) are composed of large complexes of multi-protein subunits creating ion channels in the cell plasma membranes that allow for influx or efflux of mono- or divalent cations (e.g., Ca(2+)) important for synaptic transmissions, cellular migration, and survival. Recently, we discovered the high prevalence of somatic mutations within one of the ionotropic glutamate receptors, GRIN2A, in malignant melanoma. Functional characterization of a subset of GRIN2A mutants demonstrated a loss of NMDAR complex formation between GRIN1 and GRIN2A, increased anchorage-independent growth in soft agar, and increased migration. Somatic mutation of GRIN2A results in a dominant negative effect inhibiting the tumor-suppressive phenotype of wild-type (WT) GRIN2A in melanoma. Depletion of endogenous GRIN2A in melanoma cells expressing WT GRIN2A resulted in increased proliferation compared with control. In contrast, short-hairpin RNA depletion of GRIN2A in mutant cell lines slightly reduced proliferation. Our data show that somatic mutation of GRIN2A results in increased survival, and we demonstrate the functional importance of GRIN2A mutations in melanoma and the significance that ionotropic glutamate receptor signaling has in malignant melanoma.
authors.affiliation: Cancer Genetics Branch, National Human Genetics Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Prickett
authors.affiliation: Cancer Genetics Branch, National Human Genetics Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Brad J
authors.initials: BJ
authors.lastname: Zerlanko
authors.affiliation: Cancer Genetics Branch, National Human Genetics Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Victoria K
authors.initials: VK
authors.lastname: Hill
authors.affiliation: Cancer Genetics Branch, National Human Genetics Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Gartner
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Nouar
authors.initials: N
authors.lastname: Qutob
authors.affiliation: Cancer Genetics Branch, National Human Genetics Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jiji
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: May
authors.initials: M
authors.lastname: Simaan
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: John
authors.initials: J
authors.lastname: Wunderlich
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.affiliation: Cancer Genetics Branch, National Human Genetics Research Institute, National Institutes of Health, Bethesda, Maryland, USA; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. Electronic address: Yardena.samuels@weizmann.ac.il.
authors.forename: Yardena
authors.initials: Y
authors.lastname: Samuels
mesh_terms: D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D016147:Genes, Tumor Suppressor / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; C485668:GRIN1 protein, human
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