Ligand-independent pathway that controls stability of interferon alpha receptor |
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Authors: | Liu Jianghuai Plotnikov Alexander Banerjee Anamika Suresh Kumar K G Ragimbeau Josiane Marijanovic Zrinka Baker Darren P Pellegrini Sandra Fuchs Serge Y |
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Institution: | a Department of Animal Biology and Mari Lowe Center for Comparative Oncology Research, School of Veterinary Medicine, University of Pennsylvania, Room 316 Hill Pavilion, 380 S University Avenue, Philadelphia, PA 19104-4539, USA b Unité de Signalisation des Cytokines, CNRS URA 1961, Institute Pasteur, Paris 75724, France c Biogen Idec Inc., Cambridge, MA 02142, USA |
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Abstract: | Ligand-specific negative regulation of cytokine-induced signaling relies on down regulation of the cytokine receptors. Down regulation of the IFNAR1 sub-unit of the Type I interferon (IFN) receptor proceeds via lysosomal receptor proteolysis, which is triggered by ubiquitination that depends on IFNAR1 serine phosphorylation. While IFN-inducible phosphorylation, ubiquitination, and degradation requires the catalytic activity of the Tyk2 Janus kinase, here we found the ligand- and Tyk2-independent pathway that promotes IFNAR1 phosphorylation, ubiquitination, and degradation when IFNAR1 is expressed at high levels. A major cellular kinase activity that is responsible for IFNAR1 phosphorylation in vitro does not depend on either ligand or Tyk2 activity. Inhibition of ligand-independent IFNAR1 degradation suppresses cell proliferation. We discuss the signaling events that might lead to ubiquitination and degradation of IFNAR1 via ligand-dependent and independent pathways and their potential physiologic significance. |
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Keywords: | Cytokine Interferon Receptor Ubiquitination Degradation |
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