Insulin receptor substrate 1 translocation to the nucleus by the human JC virus T-antigen.
Insulin receptor substrate 1 (IRS-1) is the major signaling molecule for the insulin and insulin-like growth factor I receptors, which transduces both metabolic and growth-promoting signals, and has transforming properties when overexpressed in the cells. Here we show that IRS-1 is translocated to the nucleus in the presence of the early viral protein-T-antigen of the human polyomavirus JC. Nuclear IRS-1 was detected in T-antigen-positive cell lines and in T-antigen-positive biopsies from patients diagnosed with medulloblastoma. The IRS-1 domain responsible for a direct JC virus T-antigen binding was localized within the N-terminal portion of IRS-1 molecule, and the binding was independent from IRS-1 tyrosine phosphorylation and was strongly inhibited by IRS-1 serine phosphorylation. In addition, competition for the IRS-1-T-antigen binding by a dominant negative mutant of IRS-1 inhibited growth and survival of JC virus T-antigen-transformed cells in anchorage-independent culture conditions. Based on these findings, we propose a novel role for the IRS-1-T-antigen complex in controlling cellular equilibrium during viral infection. It may involve uncoupling of IRS-1 from its surface receptor and translocation of its function to the nucleus.
Lassak
Adam
A
Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122, USA.
Del Valle
Luis
L
Peruzzi
Francesca
F
Wang
Jin Ying
JY
Enam
Sahnila
S
Croul
Sidney
S
Khalili
Kamel
K
Reiss
Krzysztof
K
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000941:Antigens / Q000378:metabolism; D000957:Antigens, Viral, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins; D007577:JC Virus / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000941:Antigens; D000957:Antigens, Viral, Tumor; D018076:DNA, Complementary; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D012694:Serine; D005982:Glutathione Transferase