IRS-4 mediated mitogenic signalling by insulin and growth hormone in LB cells, a murine T-cell lymphoma devoid of IGF-I receptors

• Published in: Cellular signalling Vol. 15; no. 4; pp. 385 - 394
• Main Authors: Ursø, Birgitte, Ilondo, M.Mapoko, Holst, Patricia A, Christoffersen, Claus T, Ouwens, Margriet, Giorgetti, Sophie, Van Obberghen, E, Naor, David, Tornqvist, Hans, De Meyts, Pierre
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01-04-2003
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Bell-shaped; Cattle; Enzyme Activation; ERK; Female; Growth hormone; Growth Hormone - pharmacology; Humans; Insulin; Insulin - pharmacology; Insulin Receptor Substrate Proteins; IRS-4; Lymphoma, T-Cell; Mice; Mice, Inbred BALB C; Mitogenesis; Mitogens - pharmacology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - metabolism; Phosphorylation - drug effects; PI3-kinase; Ras; Receptor, IGF Type 1 - deficiency; Signal Transduction - drug effects; STAT5; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - enzymology; Tyrosine - metabolism; GH; IGF-I; Ras; PKB; Bell-shaped; IR; PI3-kinase; IRS; MAPK; Insulin; MEK; STAT; JAK; SOS; PDK; Mitogenesis; STAT5; PI; IRS-4; Grb2; Growth hormone; SH2; ERK
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/S0898-6568(02)00113-4

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.