title: Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma.
abstract: NRAS mutation at codons 12, 13, or 61 is associated with transformation; yet, in melanoma, such alterations are nearly exclusive to codon 61. Here, we compared the melanoma susceptibility of an NrasQ61R knock-in allele to similarly designed KrasG12D and NrasG12D alleles. With concomitant p16INK4a inactivation, KrasG12D or NrasQ61R expression efficiently promoted melanoma in vivo, whereas NrasG12D did not. In addition, NrasQ61R mutation potently cooperated with Lkb1/Stk11 loss to induce highly metastatic disease. Functional comparisons of NrasQ61R and NrasG12D revealed little difference in the ability of these proteins to engage PI3K or RAF. Instead, NrasQ61R showed enhanced nucleotide binding, decreased intrinsic GTPase activity, and increased stability when compared with NrasG12D. This work identifies a faithful model of human NRAS-mutant melanoma, and suggests that the increased melanomagenecity of NrasQ61R over NrasG12D is due to heightened abundance of the active, GTP-bound form rather than differences in the engagement of downstream effector pathways.
  
  
  CONCLUSIONS
  This work explains the curious predominance in human melanoma of mutations of codon 61 of NRAS over other oncogenic NRAS mutations. Using conditional "knock-in" mouse models, we show that physiologic expression of NRASQ61R, but not NRASG12D, drives melanoma formation.
authors.affiliation: Department of Molecular Genetics, The Ohio State University, Columbus, Ohio. Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio.
authors.forename: Christin E
authors.initials: CE
authors.lastname: Burd
authors.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina. The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Wenjin
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Minh V
authors.initials: MV
authors.lastname: Huynh
authors.affiliation: Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.
authors.forename: Meriam A
authors.initials: MA
authors.lastname: Waqas
authors.affiliation: Department of Molecular Genetics, The Ohio State University, Columbus, Ohio. Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio.
authors.forename: James E
authors.initials: JE
authors.lastname: Gillahan
authors.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina. The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Clark
authors.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina. The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Kailing
authors.initials: K
authors.lastname: Fu
authors.affiliation: Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.
authors.forename: Brit L
authors.initials: BL
authors.lastname: Martin
authors.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina. The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: William R
authors.initials: WR
authors.lastname: Jeck
authors.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina. The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: George P
authors.initials: GP
authors.lastname: Souroullas
authors.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina. The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: David B
authors.initials: DB
authors.lastname: Darr
authors.affiliation: Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Zedek
authors.affiliation: Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Miley
authors.affiliation: Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand.
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Baguley
authors.affiliation: The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Campbell
authors.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina. The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina. NES@med.unc.edu.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000483:Alleles; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D003062:Codon; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017353:Gene Deletion; D023061:Gene Order; D011905:Genes, ras; D056426:Genetic Loci; D005838:Genotype; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009362:Neoplasm Metastasis; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D003062:Codon; D048049:Extracellular Signal-Regulated MAP Kinases; D006160:Guanosine Triphosphate; D020928:Mitogen-Activated Protein Kinases; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; C109790:STK11 protein, human