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 subunit of the interleukin-6 (IL-6) receptor, and a seven amino acid STAT1 recruitment motif (Y440) from the interferon (IFN)-gamma receptor, efficiently mediates an IFN-gamma-like response. An analogous completely foreign chimeric 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 phosphorylated through the chimeric receptors and the endogenous IL-6 and OSM receptors. Cross phosphorylation of IFNGR1 is not, however, required for the IFN-gamma-like response through the chimeric receptors, nor does it mediate 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 overlap between the signals generated from disparate JAK-receptor complexes and show that relatively minor changes in such complexes can profoundly affect the response.
Strobl
B
B
Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Arulampalam
V
V
Is'harc
H
H
Newman
S J
SJ
Schlaak
J F
JF
Watling
D
D
Costa-Pereira
A P
AP
Schaper
F
F
Behrmann
I
I
Sheehan
K C
KC
Schreiber
R D
RD
Horn
F
F
Heinrich
P C
PC
Kerr
I M
IM
D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D009687:Nuclear Proteins; D053633:Receptor, Interferon alpha-beta; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000096:biosynthesis / Q000378:metabolism; D000096743:Interferon gamma Receptor
D004268:DNA-Binding Proteins; D000949:Histocompatibility Antigens Class II; D007371:Interferon-gamma; D009687:Nuclear Proteins; D053633:Receptor, Interferon alpha-beta; D017467:Receptors, Erythropoietin; D011971:Receptors, Immunologic; D017471:Receptors, Interferon; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D000096743:Interferon gamma Receptor; C083728:MHC class II transactivator protein; C494079:STAT1 protein, human