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Physical and functional interaction between polyoma virus middle T antigen and insulin and IGF-I receptors is required for oncogene activation and tumour initiation.
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| Author |
R Novosyadlyy,A Vijayakumar,D Lann,Y Fierz,N Kurshan,D LeRoith |
| Citation Information |
Oncogene, 28: (2009) |
| Keywords |
Animals,Antigens, Polyomavirus Transforming,Cell Line, Tumor,Gene Knockdown Techniques,Insulin,Mammary Neoplasms, Animal,MAP Kinase Signaling System,Mice,Mice, Inbred Strains,Mice, Transgenic,Phosphatidylinositol 3-Kinases,Phosphorylation,Receptor, IGF Type 1,Receptor, Insulin |
| Related Products |
06-427 |
| Pub Med ID |
19617901 |
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Polyoma virus middle T antigen (PyVmT) is a powerful viral oncogene; however, the mechanisms of PyVmT activation are poorly understood. The insulin-like growth factor I receptor (IGF-IR) and the insulin receptor (IR) are known to be implicated in the development of many cancers. Furthermore, PyVmT-overexpressing mouse mammary carcinoma Met-1 cells are highly responsive to IGF-I and insulin. Herein, we demonstrate that PyVmT physically interacts with IGF-IR and IR in Met-1 cells. Insulin and IGF-I increase association of the IR and IGF-IR with PyVmT, enhance tyrosine phosphorylation of PyVmT and augment the recruitment of Src and PLCgamma(1) to PyVmT. This is accompanied by robust and sustained phosphorylation of Akt and ERK1/2, which are implicated in both PyVmT and IGF-IR/IR signalling. Both ligands significantly increase proliferation, survival, migration and invasion of Met-1 cells. Furthermore, orthotopic inoculation of Met-1 cells with shRNAmir-mediated knockdown of IR or IGF-IR fails to initiate tumour growth in recipient mice. In conclusion, our data indicate that the physical and functional interaction between PyVmT and cellular receptor tyrosine kinases, including IR and IGF-IR, is critical for PyVmT activation and tumour initiation. These results also provide a novel mechanism for oncogene activation in the host cell.
