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Updated: Jun 28, 2026
Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
Tnk1/Kos1 knockout mice develop spontaneous tumors
Sarasija Hoare1, Kishalay Hoare, Mary K Reinhard
1Department of Medicine, University of Florida Shands Cancer Center, Gainesville, Florida 32610-3633, USA.
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.
Insights
Tnk1/Kos1, a protein tyrosine kinase, acts as a tumor suppressor by inhibiting cell growth. Its absence leads to increased Ras activity and a higher incidence of spontaneous tumors in mice.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Tnk1/Kos1 is a non-receptor protein tyrosine kinase.
- Its catalytic activity is crucial for negatively regulating cell growth.
- Dysregulation of Tnk1/Kos1 is linked to cancer development.
Purpose of the Study:
- To investigate the role of Tnk1/Kos1 in tumor suppression.
- To elucidate the mechanism by which Tnk1/Kos1 regulates cell growth and Ras activation.
Main Methods:
- Generation of Tnk1/Kos1 null mice using homologous recombination.
- Analysis of tumor development rates in Tnk1 heterozygous and null mice.
- Assessment of Ras activation levels and Ras-guanine exchange factor (GEF) activity in Tnk1-deficient cells.
- Investigation of Tnk1/Kos1's direct interaction with Grb2.
Main Results:
- Tnk1/Kos1 null mice exhibit high rates of spontaneous lymphomas and carcinomas.
- Tnk1/Kos1 expression is silenced in tumors, associated with promoter hypermethylation.
- Tnk1/Kos1 deficiency leads to increased basal and EGF-stimulated Ras activation due to elevated Ras-GEF activity.
- Tnk1/Kos1 directly phosphorylates Grb2, disrupting the Grb2-Sos1 complex and suppressing Ras activation.
Conclusions:
- Tnk1/Kos1 functions as a tumor suppressor by down-regulating Ras activity.
- The catalytic activity of Tnk1/Kos1 is essential for its tumor-suppressive function.
- Tnk1/Kos1's mechanism involves regulating Ras-guanine exchange factor activity through Grb2 phosphorylation.
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