Affiliation:
1. From the Division of Cancer Biology, Sunnybrook Health Science Centre, Toronto; the Oncology Gene Therapy Program, The Toronto Hospital, Toronto; and the Department of Medical Biophysics, University of Toronto, Toronto, Canada.
Abstract
AbstractType I interferons (IFNs-α and IFN-β) bind to a common receptor to exert strong antiproliferative activity on a broad range of cell types, including interleukin-6 (IL-6)–dependent myeloma cells. In this study, we investigated the effect of IFN-β pretreatment on IL-6–stimulated mitogenic signaling in the human myeloma cell line U266. IL-6 induced transient tyrosine phosphorylation of the IL-6 receptor signal-transducing subunit gp130, the gp130-associated protein tyrosine kinases Jak1, Jak2, and Tyk2, the phosphotyrosine phosphatase PTP1D/Syp, the adaptor protein Shc and the mitogen-activated protein kinase Erk2, and accumulation of GTP-bound p21ras. Prior treatment of U266 cells with IFN-β downregulated IL-6–induced tyrosine phosphorylation of gp130, Jak2, PTP1D/Syp, Shc, and Erk2, and GTP-loading of p21ras. Further analysis indicated that treatment with IFN-β disrupted IL-6–induced binding of PTP1D/Syp to gp130 and the adaptor protein Grb2; IFN-β pretreatment also interfered with IL-6–induced interaction of Shc with Grb2 and a 145-kD tyrosine-phosphorylated protein. These results suggest a novel mechanism whereby type I IFNs interrupt IL-6–promoted mitogenesis of myeloma cells in part by preventing the formation of essential signaling complexes leading to p21ras activation.
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
Cited by
33 articles.
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