Ligand-independent pathway that controls stability of interferon alpha receptor

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.
Biochemical and Biophysical Research Communications (Impact Factor: 2.28). 04/2008; 367(2):388-93. DOI: 10.1016/j.bbrc.2007.12.137
Source: PubMed

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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