Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing

Nat Genet. 2011 Dec 25;44(2):165-9. doi: 10.1038/ng.1041.

Abstract

We sequenced eight melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, we found that 24% of melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 or MAP3K9. Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggest that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W333* variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Base Sequence
  • Cell Line, Tumor
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / pharmacology
  • Exome
  • Humans
  • Loss of Heterozygosity
  • MAP Kinase Kinase Kinase 5 / genetics*
  • MAP Kinase Kinase Kinases / genetics*
  • Melanoma / drug therapy
  • Melanoma / genetics*
  • Melanoma / secondary
  • Molecular Sequence Data
  • Mutation*
  • Sequence Analysis, DNA
  • Sequence Homology, Nucleic Acid
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Temozolomide
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Dacarbazine
  • MAP Kinase Kinase Kinase 5
  • MAP Kinase Kinase Kinases
  • MAP3K5 protein, human
  • MAP3K9 protein, human
  • Temozolomide

Associated data

  • PDB/2CLQ
  • PDB/2PHK
  • PDB/3DTC
  • RefSeq/NM_005204
  • RefSeq/NM_005923
  • RefSeq/NM_033141