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Biochem Biophys Res Commun. 2008 Mar 7;367(2):388-93. doi: 10.1016/j.bbrc.2007.12.137. Epub 2007 Dec 31.

Ligand-independent pathway that controls stability of interferon alpha receptor.

Author information

1
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.

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.

PMID:
18166147
PMCID:
PMC2253662
DOI:
10.1016/j.bbrc.2007.12.137
[Indexed for MEDLINE]
Free PMC Article

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