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FGF signaling regulates development by processes beyond canonical pathways

FGFs are key developmental regulators that engage a signal transduction cascade through receptor tyrosine kinases, prominently engaging ERK1/2 but also other pathways. However, it remains unknown whether all FGF activities depend on this canonical signal transduction cascade. To address this questio...

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Detalles Bibliográficos
Autores principales: Ray, Ayan T., Mazot, Pierre, Brewer, J. Richard, Catela, Catarina, Dinsmore, Colin J., Soriano, Philippe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706708/
https://www.ncbi.nlm.nih.gov/pubmed/33184218
http://dx.doi.org/10.1101/gad.342956.120
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author Ray, Ayan T.
Mazot, Pierre
Brewer, J. Richard
Catela, Catarina
Dinsmore, Colin J.
Soriano, Philippe
author_facet Ray, Ayan T.
Mazot, Pierre
Brewer, J. Richard
Catela, Catarina
Dinsmore, Colin J.
Soriano, Philippe
author_sort Ray, Ayan T.
collection PubMed
description FGFs are key developmental regulators that engage a signal transduction cascade through receptor tyrosine kinases, prominently engaging ERK1/2 but also other pathways. However, it remains unknown whether all FGF activities depend on this canonical signal transduction cascade. To address this question, we generated allelic series of knock-in Fgfr1 and Fgfr2 mouse strains, carrying point mutations that disrupt binding of signaling effectors, and a kinase dead allele of Fgfr2 that broadly phenocopies the null mutant. When interrogated in cranial neural crest cells, we identified discrete functions for signaling pathways in specific craniofacial contexts, but point mutations, even when combined, failed to recapitulate the single or double null mutant phenotypes. Furthermore, the signaling mutations abrogated established FGF-induced signal transduction pathways, yet FGF functions such as cell–matrix and cell–cell adhesion remained unaffected, though these activities did require FGFR kinase activity. Our studies establish combinatorial roles of Fgfr1 and Fgfr2 in development and uncouple novel FGFR kinase-dependent cell adhesion properties from canonical intracellular signaling.
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spelling pubmed-77067082021-06-01 FGF signaling regulates development by processes beyond canonical pathways Ray, Ayan T. Mazot, Pierre Brewer, J. Richard Catela, Catarina Dinsmore, Colin J. Soriano, Philippe Genes Dev Research Paper FGFs are key developmental regulators that engage a signal transduction cascade through receptor tyrosine kinases, prominently engaging ERK1/2 but also other pathways. However, it remains unknown whether all FGF activities depend on this canonical signal transduction cascade. To address this question, we generated allelic series of knock-in Fgfr1 and Fgfr2 mouse strains, carrying point mutations that disrupt binding of signaling effectors, and a kinase dead allele of Fgfr2 that broadly phenocopies the null mutant. When interrogated in cranial neural crest cells, we identified discrete functions for signaling pathways in specific craniofacial contexts, but point mutations, even when combined, failed to recapitulate the single or double null mutant phenotypes. Furthermore, the signaling mutations abrogated established FGF-induced signal transduction pathways, yet FGF functions such as cell–matrix and cell–cell adhesion remained unaffected, though these activities did require FGFR kinase activity. Our studies establish combinatorial roles of Fgfr1 and Fgfr2 in development and uncouple novel FGFR kinase-dependent cell adhesion properties from canonical intracellular signaling. Cold Spring Harbor Laboratory Press 2020-12-01 /pmc/articles/PMC7706708/ /pubmed/33184218 http://dx.doi.org/10.1101/gad.342956.120 Text en © 2020 Ray et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Ray, Ayan T.
Mazot, Pierre
Brewer, J. Richard
Catela, Catarina
Dinsmore, Colin J.
Soriano, Philippe
FGF signaling regulates development by processes beyond canonical pathways
title FGF signaling regulates development by processes beyond canonical pathways
title_full FGF signaling regulates development by processes beyond canonical pathways
title_fullStr FGF signaling regulates development by processes beyond canonical pathways
title_full_unstemmed FGF signaling regulates development by processes beyond canonical pathways
title_short FGF signaling regulates development by processes beyond canonical pathways
title_sort fgf signaling regulates development by processes beyond canonical pathways
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706708/
https://www.ncbi.nlm.nih.gov/pubmed/33184218
http://dx.doi.org/10.1101/gad.342956.120
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