title: Of JAKs, STATs, blind watchmakers, jeeps and trains.
abstract: Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling is essential but not sufficient for full responses to the interferons (IFNs), most cytokines and some growth factors. The IFN-gamma and interleukin-6 (IL-6) response pathways have been used as model systems to investigate both the signals involved and their organisation. Activated STAT1 diffuses freely in the cytoplasmic and nuclear compartments of the cell providing a 'random walk' element in the IFN-gamma response. Completely foreign chimeric receptors and, remarkably, in the absence of STAT3, the endogenous IL-6 receptor can efficiently mediate an IFN-gamma-like response. Accordingly all of the signals required for an IFN-gamma response can be generated through physiological levels of a foreign ligand. JAK/STAT signalling, therefore, appears 'soft-wired', modular and highly flexible with substantial overlap between different response pathways. The data are consistent with a generic or 'core' set of signals from JAK/receptor complexes with 'add-on' modulation through specific receptor motifs. The cellular background likely profoundly affects the nature of the response.
authors.affiliation: Cancer Research UK London Research Institute, Lincoln's Inn Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK. ian.kerr@cancer.org.uk
authors.forename: Ian M
authors.initials: IM
authors.lastname: Kerr
authors.forename: Ana P
authors.initials: AP
authors.lastname: Costa-Pereira
authors.forename: Björn F
authors.initials: BF
authors.lastname: Lillemeier
authors.forename: Birgit
authors.initials: B
authors.lastname: Strobl
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D008164:Luminescent Proteins / Q000378:metabolism; D008954:Models, Biological; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D000949:Histocompatibility Antigens Class II; D015850:Interleukin-6; D008164:Luminescent Proteins; D017471:Receptors, Interferon; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases