title: Drosophila SOCS36E negatively regulates JAK/STAT pathway signaling via two separable mechanisms.
abstract: Conserved from humans to Drosophila, the Janus kinase/signal transducer and activators of transcription (JAK/STAT) signaling cascade is essential for multiple developmental and homeostatic processes, with regulatory molecules controlling pathway activity also highly conserved. We characterize the Drosophila JAK/STAT pathway regulator SOCS36E and show that it functions via two independent mechanisms. First, we show that Drosophila Elongin B/C and Cullin-5 act via the SOCS-box of SOCS36E to reduce pathway activity specifically in response to ligand stimulation--a process that involves endocytic trafficking and lysosomal degradation of the Domeless (Dome) receptor. Second, SOCS36E also suppresses both stimulated and basal pathway activity via an Elongin/Cullin-independent mechanism that is mediated by the N-terminus of SOCS36E, which is required for the physical interaction of SOCS36E with Dome. Although some human SOCS proteins contain N-terminal kinase-inhibitory domains, we do not identify such a region in SOCS36E and propose a model wherein the N-terminal of SOCS36E blocks access to tyrosine residues in Dome. Our biochemical analysis of a SOCS-family regulator from a lower organism highlights the fundamental conserved roles played by regulatory mechanisms in signal transduction.
authors.affiliation: MRC Centre for Development and Biomedical Genetics and Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Stec
authors.forename: Oscar
authors.initials: O
authors.lastname: Vidal
authors.forename: Martin P
authors.initials: MP
authors.lastname: Zeidler
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000737:chemistry / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D055550:Protein Stability; D059748:Proteolysis; D018123:Receptors, Interleukin / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000737:chemistry / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: D029721:Drosophila Proteins; D050505:Mutant Proteins; D018123:Receptors, Interleukin; D050791:STAT Transcription Factors; C460659:Socs36E protein, Drosophila; D050826:Suppressor of Cytokine Signaling Proteins; C444499:dome protein, Drosophila; D053612:Janus Kinases