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Mechanisms of JAK/STAT pathway negative regulation by the short coreceptor Eye Transformer/Latran

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 dise...

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Autores principales: Fisher, Katherine H., Stec, Wojciech, Brown, Stephen, Zeidler, Martin P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751595/
https://www.ncbi.nlm.nih.gov/pubmed/26658615
http://dx.doi.org/10.1091/mbc.E15-07-0546
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author Fisher, Katherine H.
Stec, Wojciech
Brown, Stephen
Zeidler, Martin P.
author_facet Fisher, Katherine H.
Stec, Wojciech
Brown, Stephen
Zeidler, Martin P.
author_sort Fisher, Katherine H.
collection PubMed
description 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.
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spelling pubmed-47515952016-04-16 Mechanisms of JAK/STAT pathway negative regulation by the short coreceptor Eye Transformer/Latran Fisher, Katherine H. Stec, Wojciech Brown, Stephen Zeidler, Martin P. Mol Biol Cell Brief Reports 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. The American Society for Cell Biology 2016-02-01 /pmc/articles/PMC4751595/ /pubmed/26658615 http://dx.doi.org/10.1091/mbc.E15-07-0546 Text en © 2016 Fisher et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Brief Reports
Fisher, Katherine H.
Stec, Wojciech
Brown, Stephen
Zeidler, Martin P.
Mechanisms of JAK/STAT pathway negative regulation by the short coreceptor Eye Transformer/Latran
title Mechanisms of JAK/STAT pathway negative regulation by the short coreceptor Eye Transformer/Latran
title_full Mechanisms of JAK/STAT pathway negative regulation by the short coreceptor Eye Transformer/Latran
title_fullStr Mechanisms of JAK/STAT pathway negative regulation by the short coreceptor Eye Transformer/Latran
title_full_unstemmed Mechanisms of JAK/STAT pathway negative regulation by the short coreceptor Eye Transformer/Latran
title_short Mechanisms of JAK/STAT pathway negative regulation by the short coreceptor Eye Transformer/Latran
title_sort mechanisms of jak/stat pathway negative regulation by the short coreceptor eye transformer/latran
topic Brief Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751595/
https://www.ncbi.nlm.nih.gov/pubmed/26658615
http://dx.doi.org/10.1091/mbc.E15-07-0546
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