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Journal of Virology, January 2008, p. 419-427, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.01349-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Tyrosine Kinase sf-Stk and Its Downstream Signals Are Required for Maintenance of Friend Spleen Focus-Forming Virus-Induced Fibroblast Transformation{triangledown}

Tanya M. Jelacic, Delores Thompson, Charlotte Hanson, Joan L. Cmarik, Kazuo Nishigaki,{dagger} and Sandra Ruscetti*

Laboratory of Cancer Prevention, National Cancer Institute—Frederick, Frederick, Maryland 21702

Received 20 June 2007/ Accepted 15 October 2007

Infection of erythroid progenitor cells by Friend spleen focus-forming virus (SFFV) leads to acute erythroid hyperplasia and eventually to erythroleukemia in susceptible strains of mice. The viral envelope protein, SFFV gp55, forms a complex with the erythropoietin receptor (EpoR) and a short form of the receptor tyrosine kinase Stk (sf-Stk), activating both and inducing Epo-independent proliferation. Recently, we discovered that coexpression of SFFV gp55 and sf-Stk is sufficient to transform NIH 3T3 and primary fibroblasts. In the current study, we demonstrate that sf-Stk and its downstream effectors are critical to this transformation. Unlike SFFV-derived erythroleukemia cells, which depend on PU.1 expression for maintenance of the transformed phenotype, SFFV gp55-sf-Stk-transformed fibroblasts are negative for PU.1. Underscoring the importance of sf-Stk to fibroblast transformation, knockdown of sf-Stk abolished the ability of these cells to form anchorage-independent colonies. Like SFFV-infected erythroid cells, SFFV gp55-sf-Stk-transformed fibroblasts express high levels of phosphorylated MEK, ERK, phosphatidylinositol 3-kinase (PI3K), Gab1/2, Akt, Jun kinase (JNK), and STAT3, but unlike virus-infected erythroid cells they fail to express phosphorylated STATs 1 and 5, which may require involvement of the EpoR. In addition, the p38 mitogen-activated protein kinase (MAPK) stress response is suppressed in the transformed fibroblasts. Inhibition of either JNK or the PI3K pathway decreases both monolayer proliferation and anchorage-independent growth of the transformed fibroblasts as does the putative kinase inhibitor luteolin, but inhibition of p38 MAPK has no effect. Our results indicate that sf-Stk is a molecular endpoint of transformation that could be targeted directly or with agents against its downstream effectors.

* Corresponding author. Mailing address: Laboratory of Cancer Prevention, Building 469, Room 205, National Cancer Institute—Frederick, Frederick, MD 21702-1201. Phone: (301) 846-5740. Fax: (301) 846-6164. E-mail: ruscetti{at}ncifcrf.gov

{triangledown} Published ahead of print on 24 October 2007.

{dagger} Present address: Department of Veterinary Medicine, Yamaguchi University, Yamaguchi 753-8515, Japan.

Journal of Virology, January 2008, p. 419-427, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.01349-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • He, S., Ni, S., Hegde, S., Wang, X., Sharda, D. R., August, A., Paulson, R. F., Hankey, P. A. (2010). Activation of the N-Terminally Truncated Form of the Stk Receptor Tyrosine Kinase Sf-Stk by Friend Virus-Encoded gp55 Is Mediated by Cysteine Residues in the Ecotropic Domain of gp55 and the Extracellular Domain of Sf-Stk. J. Virol. 84: 2223-2235 [Abstract] [Full Text]  


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