title: Mechanisms of JAK/STAT pathway negative regulation by the short coreceptor Eye Transformer/Latran.
abstract: Transmembrane receptors interact with extracellular ligands to transduce intracellular signaling cascades, modulate target gene expression, and regulate processes such as proliferation, apoptosis, differentiation, and homeostasis. As a consequence, aberrant signaling events often underlie human disease. Whereas the vertebrate JAK/STAT signaling cascade is transduced via multiple receptor combinations, the Drosophila pathway has only one full-length signaling receptor, Domeless (Dome), and a single negatively acting receptor, Eye Transformer/Latran (Et/Lat). Here we investigate the molecular mechanisms underlying Et/Lat activity. We demonstrate that Et/Lat negatively regulates the JAK/STAT pathway activity and can bind to Dome, thus reducing Dome:Dome homodimerization by creating signaling-incompetent Dome:Et/Lat heterodimers. Surprisingly, we find that Et/Lat is able to bind to both JAK and STAT92E but, despite the presence of putative cytokine-binding motifs, does not detectably interact with pathway ligands. We find that Et/Lat is trafficked through the endocytic machinery for lysosomal degradation but at a much slower rate than Dome, a difference that may enhance its ability to sequester Dome into signaling-incompetent complexes. Our data offer new insights into the molecular mechanism and regulation of Et/Lat in Drosophila that may inform our understanding of how short receptors function in other organisms.
authors.affiliation: Bateson Centre, University of Sheffield, Sheffield S10 2TN, United Kingdom.
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Fisher
authors.affiliation: Bateson Centre, University of Sheffield, Sheffield S10 2TN, United Kingdom.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Stec
authors.affiliation: Sheffield RNAi Screening Facility, Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Brown
authors.affiliation: Bateson Centre, University of Sheffield, Sheffield S10 2TN, United Kingdom m.zeidler@sheffield.ac.uk.
authors.forename: Martin P
authors.initials: MP
authors.lastname: Zeidler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D029721:Drosophila Proteins / Q000378:metabolism / Q000502:physiology*; D004331:Drosophila melanogaster; D004705:Endocytosis; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D053612:Janus Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D011485:Protein Binding; D055550:Protein Stability; D021381:Protein Transport; D059748:Proteolysis; D018123:Receptors, Interleukin / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018123:Receptors, Interleukin; D050791:STAT Transcription Factors; C444499:dome protein, Drosophila; C554286:eye transformer protein, Drosophila; D053612:Janus Kinases