Antibody-induced dimerization of FGFR1 promotes receptor endocytosis independently of its kinase activity

Abstract Fibroblast growth factors (FGFs) and their plasma membrane-localized receptors (FGFRs) play a key role in the regulation of developmental processes and metabolism. Aberrant FGFR signaling is associated with the progression of serious metabolic diseases and human cancer. Binding of FGFs to F...

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Autores principales:	Łukasz Opaliński, Aleksandra Sokołowska-Wędzina, Martyna Szczepara, Małgorzata Zakrzewska, Jacek Otlewski
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d0a42b98f3c44e8faef0eb26810fe047
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spelling	oai:doaj.org-article:d0a42b98f3c44e8faef0eb26810fe0472021-12-02T15:06:08ZAntibody-induced dimerization of FGFR1 promotes receptor endocytosis independently of its kinase activity10.1038/s41598-017-07479-z2045-2322https://doaj.org/article/d0a42b98f3c44e8faef0eb26810fe0472017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07479-zhttps://doaj.org/toc/2045-2322Abstract Fibroblast growth factors (FGFs) and their plasma membrane-localized receptors (FGFRs) play a key role in the regulation of developmental processes and metabolism. Aberrant FGFR signaling is associated with the progression of serious metabolic diseases and human cancer. Binding of FGFs to FGFRs induces receptor dimerization and transphosphorylation of FGFR kinase domains that triggers activation of intracellular signaling pathways. Following activation, FGFRs undergo internalization and subsequent lysosomal degradation, which terminates transmission of signals. Although factors that regulate FGFR endocytosis are continuously discovered, little is known about the molecular mechanism that initiates the internalization of FGFRs. Here, we analyzed the internalization of antibody fragments in various formats that target FGFR1. We show that FGFR1-specific antibody fragments in the monovalent scFv format bind to FGFR1, but are not internalized into cells that overproduce FGFR1. In contrast, the same scFv proteins in the bivalent scFv-Fc format are efficiently internalized via FGFR1-mediated, clathrin and dynamin dependent endocytosis. Interestingly, the receptor tyrosine kinase activity is dispensable for endocytosis of scFv-Fc-FGFR1 complexes, suggesting that only dimerization of receptor is required to trigger endocytosis of FGFR1 complexes.Łukasz OpalińskiAleksandra Sokołowska-WędzinaMartyna SzczeparaMałgorzata ZakrzewskaJacek OtlewskiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Łukasz Opaliński Aleksandra Sokołowska-Wędzina Martyna Szczepara Małgorzata Zakrzewska Jacek Otlewski Antibody-induced dimerization of FGFR1 promotes receptor endocytosis independently of its kinase activity
description	Abstract Fibroblast growth factors (FGFs) and their plasma membrane-localized receptors (FGFRs) play a key role in the regulation of developmental processes and metabolism. Aberrant FGFR signaling is associated with the progression of serious metabolic diseases and human cancer. Binding of FGFs to FGFRs induces receptor dimerization and transphosphorylation of FGFR kinase domains that triggers activation of intracellular signaling pathways. Following activation, FGFRs undergo internalization and subsequent lysosomal degradation, which terminates transmission of signals. Although factors that regulate FGFR endocytosis are continuously discovered, little is known about the molecular mechanism that initiates the internalization of FGFRs. Here, we analyzed the internalization of antibody fragments in various formats that target FGFR1. We show that FGFR1-specific antibody fragments in the monovalent scFv format bind to FGFR1, but are not internalized into cells that overproduce FGFR1. In contrast, the same scFv proteins in the bivalent scFv-Fc format are efficiently internalized via FGFR1-mediated, clathrin and dynamin dependent endocytosis. Interestingly, the receptor tyrosine kinase activity is dispensable for endocytosis of scFv-Fc-FGFR1 complexes, suggesting that only dimerization of receptor is required to trigger endocytosis of FGFR1 complexes.
format	article
author	Łukasz Opaliński Aleksandra Sokołowska-Wędzina Martyna Szczepara Małgorzata Zakrzewska Jacek Otlewski
author_facet	Łukasz Opaliński Aleksandra Sokołowska-Wędzina Martyna Szczepara Małgorzata Zakrzewska Jacek Otlewski
author_sort	Łukasz Opaliński
title	Antibody-induced dimerization of FGFR1 promotes receptor endocytosis independently of its kinase activity
title_short	Antibody-induced dimerization of FGFR1 promotes receptor endocytosis independently of its kinase activity
title_full	Antibody-induced dimerization of FGFR1 promotes receptor endocytosis independently of its kinase activity
title_fullStr	Antibody-induced dimerization of FGFR1 promotes receptor endocytosis independently of its kinase activity
title_full_unstemmed	Antibody-induced dimerization of FGFR1 promotes receptor endocytosis independently of its kinase activity
title_sort	antibody-induced dimerization of fgfr1 promotes receptor endocytosis independently of its kinase activity
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/d0a42b98f3c44e8faef0eb26810fe047
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Antibody-induced dimerization of FGFR1 promotes receptor endocytosis independently of its kinase activity

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