title: Activation of a CrkL-stat5 signaling complex by type I interferons.
abstract: Type I interferons (IFNalpha and IFNbeta) transduce signals by inducing tyrosine phosphorylation of Jaks and Stats, as well as the CrkL adapter, an SH2/SH3-containing protein which provides a link to downstream pathways that mediate growth inhibition. We report that Stat5 interacts constitutively with the IFN receptor-associated Tyk-2 kinase, and during IFNalpha stimulation its tyrosine-phosphorylated form acts as a docking site for the SH2 domain of CrkL. CrkL and Stat5 then form a complex that translocates to the nucleus. This IFN-inducible CrkL-Stat5 complex binds in vitro to the TTCTAGGAA palindromic element found in the promoters of a subset of IFN-stimulated genes. Thus, during activation of the Type I IFN receptor, CrkL functions as a nuclear adapter protein and, in association with Stat5, regulates gene transcription through DNA binding.
authors.affiliation: Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors.forename: E N
authors.initials: EN
authors.lastname: Fish
authors.forename: S
authors.initials: S
authors.lastname: Uddin
authors.forename: M
authors.initials: M
authors.lastname: Korkmaz
authors.forename: B
authors.initials: B
authors.lastname: Majchrzak
authors.forename: B J
authors.initials: BJ
authors.lastname: Druker
authors.forename: L C
authors.initials: LC
authors.lastname: Platanias
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001483:Base Sequence; D001692:Biological Transport; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D008894:Milk Proteins; D009687:Nuclear Proteins / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D017931:DNA Primers; D004268:DNA-Binding Proteins; D007370:Interferon Type I; D008894:Milk Proteins; D009687:Nuclear Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators