title: Tyrosine phosphorylation of protein kinase D2 mediates ligand-inducible elimination of the Type 1 interferon receptor.
abstract: Type 1 interferons (including IFNα/β) activate their cell surface receptor to induce the intracellular signal transduction pathways that play an important role in host defenses against infectious agents and tumors. The extent of cellular responses to IFNα is limited by several important mechanisms including the ligand-stimulated and specific serine phosphorylation-dependent degradation of the IFNAR1 chain of Type 1 IFN receptor. Previous studies revealed that acceleration of IFNAR1 degradation upon IFN stimulation requires activities of tyrosine kinase TYK2 and serine/threonine protein kinase D2 (PKD2), whose recruitment to IFNAR1 is also induced by the ligand. Here we report that activation of PKD2 by IFNα (but not its recruitment to the receptor) depends on TYK2 catalytic activity. PKD2 undergoes IFNα-inducible tyrosine phosphorylation on specific phospho-acceptor site (Tyr-438) within the plekstrin homology domain. Activated TYK2 is capable of facilitating this phosphorylation in vitro. Tyrosine phosphorylation of PKD2 is required for IFNα-stimulated activation of this kinase as well as for efficient serine phosphorylation and degradation of IFNAR1 and ensuing restriction of the extent of cellular responses to IFNα.
authors.affiliation: Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Juan
authors.initials: J
authors.lastname: Qian
authors.affiliation: Biogen Idec, Inc., Cambridge, Massachusetts 02142.
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.affiliation: Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104. Electronic address: syfuchs@vet.upenn.edu.
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D000091283:Protein Kinase D2; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000276:immunology*; D053634:TYK2 Kinase / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; C507964:IFNAR1 protein, human; D016898:Interferon-alpha; D000091283:Protein Kinase D2; D053633:Receptor, Interferon alpha-beta; D014443:Tyrosine; D011494:Protein Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human