title: Activating E17K mutation in the gene encoding the protein kinase AKT1 in a subset of squamous cell carcinoma of the lung.
abstract: Somatic mutation (E17K) that constitutively activates the protein kinase AKT1 has been found in human cancer patients. We determined the role of the E17K mutation of AKT1 in lung cancer, through sequencing of AKT1 exon 4 in 105 resected, clinically annotated non-small cell lung cancer specimens. We detected a missense mutations G-->A transition at nucleotide 49 (that results in the E17K substitution) in two squamous cell carcinoma (2/36) but not in adenocarcinoma (0/53). The activity of the endogenous kinase carrying the E17K mutation immunoprecipitated by tumour tissue was significantly higher compared with the wild-type kinase immunoprecipitated by the adjacent normal tissue as determined both by in vitro kinase assay using a consensus peptide as substrate and by in vivo analysis of the phosphorylation status of AKT1 itself (pT308, pS473) or of known downstream substrates such as GSK3 (pS9/S22) and p27 (T198). Immunostaining or immunoblot analysis on membrane-enriched extracts indicated that the enhanced membrane localization exhibited by the endogenous E17K-AKT1 may account for the observed increased activity of mutant E17K kinase in comparison with the wild-type AKT1 from adjacent normal tissue. In conclusion, this is the first report of AKT1 mutation in lung cancer. Our data provide evidence that, although AKT1 mutations are apparently rare in lung cancer (1.9%), the oncogenic properties of E17K-AKT1 may contribute to the development of a fraction of lung carcinoma with squamous histotype (5.5%).
authors.affiliation: Laboratorio di Oncologia Molecolare, BioGem s.c. a r.l., Ariano Irpino (AV), Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Malanga
authors.forename: Marianna
authors.initials: M
authors.lastname: Scrima
authors.forename: Carmela
authors.initials: C
authors.lastname: De Marco
authors.forename: Fernanda
authors.initials: F
authors.lastname: Fabiani
authors.forename: Nicla
authors.initials: N
authors.lastname: De Rosa
authors.forename: Silvia
authors.initials: S
authors.lastname: De Gisi
authors.forename: Natalia
authors.initials: N
authors.lastname: Malara
authors.forename: Rocco
authors.initials: R
authors.lastname: Savino
authors.forename: Gaetano
authors.initials: G
authors.lastname: Rocco
authors.forename: Gennaro
authors.initials: G
authors.lastname: Chiappetta
authors.forename: Renato
authors.initials: R
authors.lastname: Franco
authors.forename: Virginia
authors.initials: V
authors.lastname: Tirino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pirozzi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viglietto
mesh_terms: D000368:Aged; D019943:Amino Acid Substitution; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics*; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics*; D008239:Lysine / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism
chemical_list: D018698:Glutamic Acid; D051057:Proto-Oncogene Proteins c-akt; D008239:Lysine