title: Ligand-independent pathway that controls stability of interferon alpha receptor.
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.
authors.affiliation: 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.
authors.forename: Jianghuai
authors.initials: J
authors.lastname: Liu
authors.forename: Alexander
authors.initials: A
authors.lastname: Plotnikov
authors.forename: Anamika
authors.initials: A
authors.lastname: Banerjee
authors.forename: K G
authors.initials: KG
authors.lastname: Suresh Kumar
authors.forename: Josiane
authors.initials: J
authors.lastname: Ragimbeau
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Marijanovic
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.forename: Sandra
authors.initials: S
authors.lastname: Pellegrini
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008024:Ligands; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: C507964:IFNAR1 protein, human; D008024:Ligands; D025801:Ubiquitin; D053633:Receptor, Interferon alpha-beta