IRS-4 mediated mitogenic signalling by insulin and growth hormone in LB cells, a murine T-cell lymphoma devoid of IGF-I receptors.
Insulin and growth hormone (GH) induce mitogenic and metabolic signals in cells, GH either directly or indirectly via IGF-I production. We have studied a spontaneous murine T-cell lymphoma (LB cells) devoid of IGF-1 receptors in which proliferation is maintained by insulin [Int. J. Cancer 50 (1992) 80], and show that GH is more potent than insulin, with both GH and insulin dose-response curves for thymidine incorporation being bell-shaped. Binding showed somatogenic rather than lactogenic GH receptors. Insulin stimulated phosphorylation of the insulin receptor and of a 160-kDa protein, identified as the IRS-4 protein. This phosphorylated IRS-4 associated with PI3-kinase, which was activated along with the downstream p70(S6) kinase, whereas the Ras-MAPK pathway was not. Using selective inhibitors, the PI3-kinase, but not p70(S6) kinase or MEK, was found to be involved in insulin-stimulated DNA synthesis. GH induced tyrosine phosphorylation of IRS-4 and nuclear translocation of STAT5. The LB cells constitute a new model for studying GH and insulin signalling without interference of IGF-1 receptors.
Ursø
Birgitte
B
Department of Receptor Biology, Hagedorn Research Institute, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark. bur@novonordisk.com
Ilondo
M Mapoko
MM
Holst
Patricia A
PA
Christoffersen
Claus T
CT
Ouwens
Margriet
M
Giorgetti
Sophie
S
Van Obberghen
E
E
Naor
David
D
Tornqvist
Hans
H
De Meyts
Pierre
P
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002417:Cattle; D004789:Enzyme Activation; D005260:Female; D013006:Growth Hormone / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D016399:Lymphoma, T-Cell; D051379:Mice; D008807:Mice, Inbred BALB C; D008934:Mitogens / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000172:deficiency; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D013006:Growth Hormone; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008934:Mitogens; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D017526:Receptor, IGF Type 1; D014443:Tyrosine; C107686:IRS4 protein, human; C491531:Irs4 protein, mouse