Physical and functional interaction between polyoma virus middle T antigen and insulin and IGF-I receptors is required for oncogene activation and tumour initiation

Abstract

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 PLCγ₁ 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.