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

• Published in: Oncogene Vol. 28; no. 39; pp. 3477 - 3486
• Main Authors: Novosyadlyy, R, Vijayakumar, A, Lann, D, Fierz, Y, Kurshan, N, LeRoith, D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2009; Nature Publishing Group
• Subjects: AKT protein; Animals; Antigens; Antigens, Polyomavirus Transforming - metabolism; Apoptosis; Biological and medical sciences; Breast cancer; c-Met protein; Carcinoma; Cell activation; Cell Biology; Cell Line, Tumor; Cell migration; Cell physiology; Cell proliferation; Cell receptors; Cell structures and functions; Cell survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular signal transduction; Data processing; Extracellular signal-regulated kinase; Fundamental and applied biological sciences. Psychology; Gene Knockdown Techniques; Genetic aspects; Genetics; Growth factor receptors; Health aspects; Human Genetics; Infectious diseases; Inoculation; Insulin; Insulin - metabolism; Insulin receptors; Insulin-like growth factor I; Insulin-like growth factor I receptors; Insulin-like growth factors; Internal Medicine; Mammary gland; Mammary Neoplasms, Animal - metabolism; MAP Kinase Signaling System; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Inbred Strains; Mice, Transgenic; Miscellaneous; Molecular and cellular biology; Oncogenes; Oncology; original-article; Phosphatidylinositol 3-Kinases - metabolism; Phospholipase C; Phosphorylation; Physiological aspects; Polyoma virus; Polyomavirus; Protein tyrosine kinase; Protein-tyrosine kinase receptors; Receptor, IGF Type 1 - metabolism; Receptor, Insulin - metabolism; Rodents; Signal transduction; Src protein; Tumors; Tyrosine; Viral diseases; Viruses; United States; polyoma virus middle T oncogene; oncogenes; IGF-I receptor; insulin receptor; crosstalk; Pancreatic hormone; Crosstalk; Activation; Insulin like growth factor 1; Carcinogenesis; Insulin; Infection; Viral disease; Tumor; Onc gene; Initiation; Middle T antigen; Biological receptor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2009.209

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 PLCγ 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.