Friend spleen focus-forming virus transforms rodent fibroblasts in cooperation with a short form of the receptor tyrosine kinase Stk.
Friend spleen focus-forming virus (SFFV) causes rapid erythroleukemia in mice due to expression of its unique envelope glycoprotein, gp55. Erythroid cells expressing SFFV gp55 proliferate in the absence of their normal regulator erythropoietin (Epo) because of constitutive activation of Epo signal transduction pathways. Although SFFV infects many cell types, deregulation of cell growth occurs only when SFFV infects erythroid cells, suggesting that these cells express unique proteins that the virus requires to mediate its biological effects. Not only do erythroid cells express the Epo receptor (EpoR), but those from mice susceptible to SFFV-induced erythroleukemia also express a short form of the receptor tyrosine kinase Stk (sf-Stk). In erythroid cells, SFFV gp55 interacts with the EpoR complex and sf-Stk, leading to activation of the kinase and constitutive activation of signal transducing molecules. In this study, we demonstrate that SFFV gp55 can also deregulate the growth of nonerythroid cells when it is coexpressed with sf-Stk. Expression of SFFV gp55 in rodent fibroblasts engineered to express sf-Stk induced their transformation, as demonstrated by focus formation and anchorage-independent growth in vitro. This transformation by SFFV gp55 requires the kinase activity of sf-Stk and the presence of its extracellular domain but not expression of the EpoR or the tyrosine kinase Jak2, which is required for activation of signal transduction pathways through the EpoR. Thus, expression of SFFV gp55 in nonerythroid cells coexpressing sf-Stk results in their uncontrolled growth, demonstrating a previously unrecognized mechanism for retrovirus transformation of rodent fibroblasts and providing insight into SFFV-induced disease.
Nishigaki
Kazuo
K
Laboratory of Cancer Prevention, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Hanson
Charlotte
C
Jelacic
Tanya
T
Thompson
Delores
D
Ruscetti
Sandra
S
D000818:Animals; D002472:Cell Transformation, Viral; D005347:Fibroblasts / Q000166:cytology; D053614:Janus Kinase 2; D051379:Mice; D041681:NIH 3T3 Cells; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000502:physiology*; D013155:Spleen Focus-Forming Viruses / Q000472:pathogenicity*; D014759:Viral Envelope Proteins / Q000502:physiology
D011518:Proto-Oncogene Proteins; D014759:Viral Envelope Proteins; C078780:glycoprotein gp55, Friend spleen focus-forming virus; D011505:Protein-Tyrosine Kinases; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2