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Transforming mechanism of the feline sarcoma virus encoded v-fms oncogene product
T Tamura1, A Hadwiger-Fangmeier, E Simon
1Institut für Virologie, Justus-Liebig-Universität Giessen, Germany.
Abstract:
The v-fms oncogene product encoded by the McDonough strain of feline sarcoma virus (SM-FeSV) is a transmembrane glycoprotein which belongs to the tyrosine kinase receptor family. The cellular counterpart, the c-fms product, is the receptor for macrophage colony stimulating factor (M-CSF or CSF-1). The v-fms and the c-fms product differ structurally only in seven point mutations and in their C-terminal domains. We have corrected the published sequence of the v-fms product and found that the new C-terminal end contains a threonine phosphorylation site (Thr939). This site is phosphorylated in vivo leading to an enhancement of the v-fms-specific tyrosine kinase activity. The extracellular domain of the v-fms product contains 11 N-glycosylation sites. Glycosylation and transport of the v-fms molecules to the plasma membrane are prerequisites for the transforming potential of the virus. Phosphorylation of the v-fms molecules in tyrosine, serine and threonine residues takes place only at the plasma membrane. Coexpression showed that the overexpression of M-CSF and c-fms in fibroblasts leads to cell transformation by an autocrine loop mechanism. This interaction between M-CSF and the c-fms protein also takes place at the plasma membrane. To study the v-fms transforming mechanisms, we have expressed the v-fms oncogene in chicken fibroblasts which are free of the cross-reactive M-CSF. The expression of the v-fms oncogene alone did not cause transformation. However, upon addition of M-CSF, these cells became completely transformed.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
The feline sarcoma virus v-fms oncogene product, a tyrosine kinase receptor, is activated by phosphorylation at a novel threonine site. Macrophage colony-stimulating factor (M-CSF) drives v-fms-mediated cell transformation.
Area of Science:
- Molecular Biology
- Virology
- Oncology
Background:
- The v-fms oncogene product from feline sarcoma virus is a transmembrane glycoprotein in the tyrosine kinase receptor family.
- Its cellular counterpart, c-fms, functions as the receptor for macrophage colony-stimulating factor (M-CSF).
Purpose of the Study:
- To elucidate the transforming mechanisms of the v-fms oncogene.
- To investigate the role of post-translational modifications and M-CSF in v-fms-mediated cell transformation.
Main Methods:
- Corrected the published sequence of the v-fms product to identify a novel C-terminal threonine phosphorylation site (Thr939).
- Expressed the v-fms oncogene in chicken fibroblasts lacking endogenous M-CSF.
- Assessed cell transformation upon addition of M-CSF.
Main Results:
- Phosphorylation at Thr939 enhances v-fms-specific tyrosine kinase activity.
- N-glycosylation and plasma membrane transport of v-fms are essential for viral transforming potential.
- v-fms expression alone did not transform M-CSF-free fibroblasts, but M-CSF addition induced complete transformation.
Conclusions:
- Phosphorylation of v-fms at Thr939 is a key regulatory mechanism enhancing its kinase activity.
- M-CSF is crucial for v-fms-mediated cell transformation, acting via an autocrine loop mechanism with c-fms.
- The v-fms oncogene requires M-CSF for its transforming activity, highlighting the importance of the M-CSF/c-fms signaling pathway in oncogenesis.