title: Tnk1/Kos1 knockout mice develop spontaneous tumors.
abstract: Tnk1/Kos1 is a non-receptor protein tyrosine kinase implicated in negatively regulating cell growth in a mechanism requiring its intrinsic catalytic activity. Tnk1/Kos1 null mice were created by homologous recombination by deleting the catalytic domain. Both Tnk1(+/-) and Tnk1(-/-) mice develop spontaneous tumors, including lymphomas and carcinomas, at high rates [27% (14 of 52) and 43% (12 of 28), respectively]. Tnk1/Kos1 expression is silenced in tumors that develop in Tnk1(+/-) mice but not in adjacent uninvolved tissue, and silencing occurs in association with Tnk1 promoter hypermethylation. Tissues and murine embryonic fibroblasts derived from Tnk1/Kos1-null mice exhibit proportionally higher levels of basal and epidermal growth factor-stimulated Ras activation that results from increased Ras-guanine exchange factor (GEF) activity. Mechanistically, Tnk1/Kos1 can directly tyrosine phosphorylate growth factor receptor binding protein 2 (Grb2), which promotes disruption of the Grb2-Sos1 complex that mediates growth factor-induced Ras activation, providing dynamic regulation of Ras GEF activity with suppression of Ras. Thus, Tnk1/Kos1 is a tumor suppressor that functions to down-regulate Ras activity.
authors.affiliation: Department of Medicine, University of Florida Shands Cancer Center, Gainesville, Florida 32610-3633, USA.
authors.forename: Sarasija
authors.initials: S
authors.lastname: Hoare
authors.forename: Kishalay
authors.initials: K
authors.lastname: Hoare
authors.forename: Mary K
authors.initials: MK
authors.lastname: Reinhard
authors.forename: Young J
authors.initials: YJ
authors.lastname: Lee
authors.forename: S Paul
authors.initials: SP
authors.lastname: Oh
authors.forename: W Stratford
authors.initials: WS
authors.lastname: May
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D017931:DNA Primers; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D018390:Gene Targeting; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*
chemical_list: D017931:DNA Primers; D011505:Protein-Tyrosine Kinases; C475466:Kos1 protein, mouse