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 spon...

Full description

Saved in:
Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2008-11, Vol.68 (21), p.8723-8732
Main Authors: Hoare, Sarasija, Hoare, Kishalay, Reinhard, Mary K, Lee, Young J, Oh, S Paul, May, Jr, W Stratford
Format: Article
Language:English
Subjects:
Alleles
Animals
Base Sequence
Blotting, Western
Cells, Cultured
DNA Primers
Epigenesis, Genetic
Gene Silencing
Gene Targeting
Immunoprecipitation
Mice
Mice, Knockout
Neoplasms, Experimental - genetics
Protein-Tyrosine Kinases - genetics
Protein-Tyrosine Kinases - physiology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-08-1467