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Kos1, a nonreceptor tyrosine kinase that suppresses Ras signaling

Oncogene volume 22, pages 3562–3577 (2003)Cite this article

Abstract

Kinase of embryonic stem cells (Kos1), a nonreceptor protein tyrosine kinase (NRPTK), was identified and cloned from differentiating murine embryonic stem cells. Kos1 is localized on mouse chromosome 11 that corresponds to human chromosome 17p13.1 and is homologous to Tnk1, Ack1 and Ack2, making it a new member of the Ack family of NRPTKs. Kos1 is a ubiquitously expressed 47-kDa protein with autotyrosine kinase activity that is developmentally regulated during embryogenesis. Kos1 is also upregulated following IL3 withdrawal from factor-dependent murine NSF/N1.H7 cells that undergo apoptosis, suggesting a role in growth inhibition. Stable overexpression of Kos1 inhibits growth of NIH 3T3 cells, while the kinase-dead Kos1(CN) promotes cell growth in both liquid culture and soft agar. In addition, forced expression of Kos1 inhibits Ras activity in an indirect mechanism that results in the downregulation of the Ras–Raf1–MAPK growth pathway. Furthermore, overexpression of Kos1 in NCI-H82 lung cancer cells that express oncogenic Ha-Ras(G12V) inhibits cell growth under reduced serum (0.5%) conditions in close association with the upregulation of the Ras inhibitor, Rap1A. Collectively, these data support a negative regulatory role for Kos1 in regulating the Ras–Raf1–MAPK growth pathway by a mechanism that requires its autotyrosine kinase activity.

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Acknowledgements

We are grateful to Drs NG Copeland and NA Jenkins for determining the chromosomal localization of Kos1. We thank Dr L Xiao for NCI-H82:Ras(G12V) cells. We thank Drs P Raychaudhuri, T Ito and R Miflin for their advice and fruitful discussions. This work is supported in part by the National Institute of Health Grants CA44649 and HL5408.

Accession number

GenBank database, Accession numbers for Kos1 sequences are AF307745 and AF307746.

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  1. Orla M Smith

    Present address: Science, 1200 New York Ave, NW, Washington, DC, 20005, USA

Authors and Affiliations

  1. University of Florida Shands Cancer Center, 1600 SW Archer Road, Gainesville, 32610-0232, FL, USA

    Kishalay Hoare, Sarasija Hoare & W Stratford May Jr

  2. Sealy Center for Oncology and Hematology, University of Texas Medical Branch, Galveston, 77555, TX, USA

    Orla M Smith & Grace Kalmaz

  3. Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, 21287-5001, MD, USA

    Donald Small

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Correspondence to W Stratford May Jr.

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Hoare, K., Hoare, S., Smith, O. et al. Kos1, a nonreceptor tyrosine kinase that suppresses Ras signaling. Oncogene 22, 3562–3577 (2003). https://doi.org/10.1038/sj.onc.1206480

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