Nuclear translocation of insulin receptor substrate-1 by the simian virus 40 T antigen and the activated type 1 insulin-like growth factor receptor.
32D cells are a murine hemopoietic cell line that undergoes apoptosis upon withdrawal of interleukin-3 (IL-3) from the medium. 32D cells have low levels of the type 1 insulin-like growth factor (IGF-I) receptor and do not express insulin receptor substrate-1 (IRS-1) or IRS-2. Ectopic expression of IRS-1 delays apoptosis but cannot rescue 32D cells from IL-3 dependence. In 32D/IRS-1 cells, IRS-1 is detectable, as expected, in the cytosol/membrane compartment. The SV40 large T antigen is a nuclear protein that, by itself, also fails to protect 32D cells from apoptosis. Co-expression of IRS-1 with the SV40 T antigen in 32D cells results in nuclear translocation of IRS-1 and survival after IL-3 withdrawal. Expression of a human IGF-I receptor in 32D/IRS-1 cells also results in nuclear translocation of IRS-1 and IL-3 independence. The phosphotyrosine-binding domain, but not the pleckstrin domain, is necessary for IRS-1 nuclear translocation. Nuclear translocation of IRS-1 was confirmed in mouse embryo fibroblasts. These results suggest possible new roles for nuclear IRS-1 in IGF-I-mediated growth and anti-apoptotic signaling.
Prisco
Marco
M
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Santini
Francesca
F
Baffa
Raffaele
R
Liu
Mingli
M
Drakas
Robert
R
Wu
An
A
Baserga
Renato
R
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D021381:Protein Transport; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D013601:T-Lymphocytes; D014162:Transfection
D000952:Antigens, Polyomavirus Transforming; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D011994:Recombinant Proteins; D017526:Receptor, IGF Type 1