Tnk1/Kos1 knockout mice develop spontaneous tumors.
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.
Hoare
Sarasija
S
Department of Medicine, University of Florida Shands Cancer Center, Gainesville, Florida 32610-3633, USA.
Hoare
Kishalay
K
Reinhard
Mary K
MK
Lee
Young J
YJ
Oh
S Paul
SP
May
W Stratford
WS
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*
D017931:DNA Primers; D011505:Protein-Tyrosine Kinases; C475466:Kos1 protein, mouse