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Tnk1/Kos1 Knockout Mice Develop Spontaneous Tumors

¹ Department of Medicine, University of Florida Shands Cancer Center; ² Department of Infectious Disease and Pathology, College of Veterinary Medicine and ³ Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida

Requests for reprints: W. Stratford May, University of Florida Shands Cancer Center, 1376 Mowry Road, Gainesville, FL 32610-3633. Phone: 352-273-8014; Fax: 352-273-8285; E-mail: smay{at}medicine.ufl.edu.

Key Words: Non–receptor protein tyrosine kinase (NRPTK) • Kinase of embryonic stem cells (Kos1) • Thirty-eight negative kinase1 (Tnk1) • Ras • Grb2 • Spontaneous tumors • Loss of heterozygosity (LOH)

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. [Cancer Res 2008;68(21):8723–32]

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