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Sf-Stk kinase activity and the Grb2 binding site are required for Epo-independent growth of primary erythroblasts infected with Friend virus

Oncogene volume 21, pages 3562–3570 (2002)Cite this article

Abstract

During the initial stage of Friend virus-induced erythroleukemia in mice, interaction of the viral protein gp55 with the erythropoietin receptor, and other host factors, drives the expansion of erythroid precursor cells. Recently, we demonstrated that the Friend virus susceptibility locus, Fv2, which is required for the expansion of infected cells, encodes a naturally occurring, N-terminally truncated form of the Stk receptor tyrosine kinase (Sf-Stk). Here we show that in vitro expression of Sf-Stk confers Friend virus sensitivity to erythroid progenitor cells from Fv2rr mice. Furthermore, our data reveal that Sf-Stk kinase activity and Y436, but not Y429, are required for Epo-independent colony formation following Friend virus infection. Introduction of a mutation that results in failure to bind Grb2 abrogates the ability of Sf-Stk to induce colonies in response to Friend virus, while the Grb2 binding site from EGFR restores this response. Consistent with the ability of Grb2 to recruit SOS and Gab1, the Ras/MAPK and PI3K pathways are activated by Sf-Stk, and both of these pathways are required for gp55-mediated erythroblast proliferation. These data clearly demonstrate a requirement for signaling through Sf-Stk in the Epo-independent expansion of Friend virus-infected cells, and suggest a pivotal role for Grb2 in this response.

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Acknowledgements

The authors would like to thank Drs A August and A Henderson for their technical advice concerning autophosphorylation studies and retroviral transduction techniques and Dr T Suda for the Stk docking site tyrosine mutant constructs. This work was supported in part by an American Cancer Society Postdoctoral Fellowship PF-01-121-01-LIB (LD Finkelstein), National Institutes of Health (NIH) grant RO1 HL66471 (PH Correll and RF Paulson), and a Junior Faculty Scholar Award from the American Society of Hematology (PH Correll).

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Authors and Affiliations

  1. Department of Veterinary Science, The Pennsylvania State University, University Park, 16802, Pennsylvania, PA, USA

    Lisa D Finkelstein, Qing-Ping Liu, Robert F Paulson & Pamela H Correll

  2. Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, 38105, Tennessee, TN, USA

    Paul A Ney

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  1. Lisa D Finkelstein
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  2. Paul A Ney
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Correspondence to Pamela H Correll.

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Finkelstein, L., Ney, P., Liu, QP. et al. Sf-Stk kinase activity and the Grb2 binding site are required for Epo-independent growth of primary erythroblasts infected with Friend virus. Oncogene 21, 3562–3570 (2002). https://doi.org/10.1038/sj.onc.1205442

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