Physical and functional interaction between polyoma virus middle T antigen and insulin and IGF-I receptors is required for oncogene activation and tumour initiation
| Autor: | N Kurshan, Ruslan Novosyadlyy, D. Lann, Derek LeRoith, Archana Vijayakumar, Yvonne Fierz |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
medicine.medical_specialty MAP Kinase Signaling System oncogenes viruses medicine.medical_treatment Antigens Polyomavirus Transforming Mammary Neoplasms Animal Mice Inbred Strains Mice Transgenic Biology medicine.disease_cause Article Receptor IGF Type 1 crosstalk 03 medical and health sciences Mice Phosphatidylinositol 3-Kinases 0302 clinical medicine Antigen Internal medicine Cell Line Tumor Genetics medicine Animals Insulin Phosphorylation insulin receptor Receptor neoplasms Molecular Biology Pancreatic hormone 030304 developmental biology 0303 health sciences Receptor Insulin 3. Good health polyoma virus middle T oncogene Insulin receptor Endocrinology 030220 oncology & carcinogenesis Gene Knockdown Techniques Cancer research biology.protein Viral disease Carcinogenesis IGF-I receptor |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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