A completely foreign receptor can mediate an interferon-gamma-like response

A tripartite receptor comprising the external region of the erythropoietin (Epo) receptor, the transmembrane and JAK-binding domains of the gp130 subu nit of the interleukin-6 (IL-6) receptor, and a seven amino acid STAT1. rec ruitment motif (Y440) from the interferon (IFN)-gamma receptor, efficiently mediates an IFN-gamma -like response. An analogous completely foreign chim eric receptor in which the Y440 motif is replaced with the Y905 motif from gp130 also mediates an IFN-gamma -like response, but less efficiently. The IFNGR1 signal-transducing subunit of the IFN-gamma receptor is tyrosine pho sphorylated through the chimeric receptors and the endogenous IL-6 and OSM receptors. Cross phosphorylation of IFNGR1 is not, however, required for th e IFN-gamma -like response through the chimeric receptors, nor does it medi ate an IFN-gamma -like response to IL-6 or OSM. The data argue strongly for modular JAK/STAT signalling and against any rigid structural organization for the 'pathways' involved. They emphasize the likely high degree of overl ap between the signals generated from disparate JAK-receptor complexes and show that relatively minor changes in such complexes can profoundly affect the response.