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Receptor clustering by a precise set of extracellular galectins initiates FGFR signaling
FGF/FGFR signaling is critical for the development and homeostasis of the human body and imbalanced FGF/FGFR contributes to the progression of severe diseases, including cancers. FGFRs are N-glycosylated, but the role of these modifications is largely unknown. Galectins are extracellular carbohydrat...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10070233/ https://www.ncbi.nlm.nih.gov/pubmed/37012400 http://dx.doi.org/10.1007/s00018-023-04768-x |
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author | Zukowska, Dominika Gedaj, Aleksandra Porebska, Natalia Pozniak, Marta Krzyscik, Mateusz Czyrek, Aleksandra Krowarsch, Daniel Zakrzewska, Malgorzata Otlewski, Jacek Opalinski, Lukasz |
author_facet | Zukowska, Dominika Gedaj, Aleksandra Porebska, Natalia Pozniak, Marta Krzyscik, Mateusz Czyrek, Aleksandra Krowarsch, Daniel Zakrzewska, Malgorzata Otlewski, Jacek Opalinski, Lukasz |
author_sort | Zukowska, Dominika |
collection | PubMed |
description | FGF/FGFR signaling is critical for the development and homeostasis of the human body and imbalanced FGF/FGFR contributes to the progression of severe diseases, including cancers. FGFRs are N-glycosylated, but the role of these modifications is largely unknown. Galectins are extracellular carbohydrate-binding proteins implicated in a plethora of processes in heathy and malignant cells. Here, we identified a precise set of galectins (galectin-1, -3, -7, and -8) that directly interact with N-glycans of FGFRs. We demonstrated that galectins bind N-glycan chains of the membrane-proximal D3 domain of FGFR1 and trigger differential clustering of FGFR1, resulting in activation of the receptor and initiation of downstream signaling cascades. Using engineered galectins with controlled valency, we provide evidence that N-glycosylation-dependent clustering of FGFR1 constitutes a mechanism for FGFR1 stimulation by galectins. We revealed that the consequences of galectin/FGFR signaling for cell physiology are markedly different from the effects induced by canonical FGF/FGFR units, with galectin/FGFR signaling affecting cell viability and metabolic activity. Furthermore, we showed that galectins are capable of activating an FGFR pool inaccessible for FGF1, enhancing the amplitude of transduced signals. Summarizing, our data identify a novel mechanism of FGFR activation, in which the information stored in the N-glycans of FGFRs provides previously unanticipated information about FGFRs’ spatial distribution, which is differentially deciphered by distinct multivalent galectins, affecting signal transmission and cell fate. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-023-04768-x. |
format | Online Article Text |
id | pubmed-10070233 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-100702332023-04-05 Receptor clustering by a precise set of extracellular galectins initiates FGFR signaling Zukowska, Dominika Gedaj, Aleksandra Porebska, Natalia Pozniak, Marta Krzyscik, Mateusz Czyrek, Aleksandra Krowarsch, Daniel Zakrzewska, Malgorzata Otlewski, Jacek Opalinski, Lukasz Cell Mol Life Sci Original Article FGF/FGFR signaling is critical for the development and homeostasis of the human body and imbalanced FGF/FGFR contributes to the progression of severe diseases, including cancers. FGFRs are N-glycosylated, but the role of these modifications is largely unknown. Galectins are extracellular carbohydrate-binding proteins implicated in a plethora of processes in heathy and malignant cells. Here, we identified a precise set of galectins (galectin-1, -3, -7, and -8) that directly interact with N-glycans of FGFRs. We demonstrated that galectins bind N-glycan chains of the membrane-proximal D3 domain of FGFR1 and trigger differential clustering of FGFR1, resulting in activation of the receptor and initiation of downstream signaling cascades. Using engineered galectins with controlled valency, we provide evidence that N-glycosylation-dependent clustering of FGFR1 constitutes a mechanism for FGFR1 stimulation by galectins. We revealed that the consequences of galectin/FGFR signaling for cell physiology are markedly different from the effects induced by canonical FGF/FGFR units, with galectin/FGFR signaling affecting cell viability and metabolic activity. Furthermore, we showed that galectins are capable of activating an FGFR pool inaccessible for FGF1, enhancing the amplitude of transduced signals. Summarizing, our data identify a novel mechanism of FGFR activation, in which the information stored in the N-glycans of FGFRs provides previously unanticipated information about FGFRs’ spatial distribution, which is differentially deciphered by distinct multivalent galectins, affecting signal transmission and cell fate. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-023-04768-x. Springer International Publishing 2023-04-03 2023 /pmc/articles/PMC10070233/ /pubmed/37012400 http://dx.doi.org/10.1007/s00018-023-04768-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article Zukowska, Dominika Gedaj, Aleksandra Porebska, Natalia Pozniak, Marta Krzyscik, Mateusz Czyrek, Aleksandra Krowarsch, Daniel Zakrzewska, Malgorzata Otlewski, Jacek Opalinski, Lukasz Receptor clustering by a precise set of extracellular galectins initiates FGFR signaling |
title | Receptor clustering by a precise set of extracellular galectins initiates FGFR signaling |
title_full | Receptor clustering by a precise set of extracellular galectins initiates FGFR signaling |
title_fullStr | Receptor clustering by a precise set of extracellular galectins initiates FGFR signaling |
title_full_unstemmed | Receptor clustering by a precise set of extracellular galectins initiates FGFR signaling |
title_short | Receptor clustering by a precise set of extracellular galectins initiates FGFR signaling |
title_sort | receptor clustering by a precise set of extracellular galectins initiates fgfr signaling |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10070233/ https://www.ncbi.nlm.nih.gov/pubmed/37012400 http://dx.doi.org/10.1007/s00018-023-04768-x |
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