J Biol Chem, Vol. 273, Issue 10, 5577-5581, March 6, 1998

Identification of a Domain in the  Subunit of the Type I Interferon (IFN) Receptor That Exhibits a Negative Regulatory Effect in the Growth Inhibitory Action of Type I IFNs

Leonidas C. Platanias, Paul Domanski^§, Owen W. Nadeau^§, Taolin Yi^¶, Shahab Uddin, Eleanor Fish, Benjamin G. Neel^**, and Oscar R. Colamonici^§

From the  Section of Hematology/Oncology, University of Illinois at Chicago, and West Side Veterans Affairs Hospital, Chicago, Illinois 60607, the ^§ Department of Pathology, University of Tennessee, Memphis, Tennessee 38163, the ^¶ Department of Cancer Biology, The Cleveland Clinic Foundation Research Institute, Cleveland, Ohio 44195, the  Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada, and the ^** Cancer Biology Program, Division of Hematology-Oncology, Department of Medicine, Beth Israel Hospital, Boston, Massachusetts 02215

Expression of human  and long form of the  (_L) subunits of type I interferon receptor (IFN-R) in mouse cells is sufficient to activate the Jak-Stat pathway and to elicit an antiviral state in response to human IFN2 and IFN. We demonstrate herein, however, that these cells respond to the antiproliferative effects of murine IFN but not human type I IFNs. These results suggest that an unknown species-specific component is required for the antiproliferative effect of human type I IFNs. The absence of this component can be complemented by expressing the human _L chain truncated at amino acid 346. Thus, the distal region of _L appears to function as a negative regulator of the growth inhibitory effects of type I IFNs. Further studies looking for possible targets of the _L regulatory domain demonstrated that this region associates with a tyrosine phosphatase. These results suggest that a protein associated with the negative regulatory domain of _L, likely a tyrosine phosphatase, plays a role in regulating the growth inhibitory effects of human type I IFNs.