{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T11:21:04Z","timestamp":1787570464805,"version":"build-2736575974"},"reference-count":100,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T00:00:00Z","timestamp":1712102400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T00:00:00Z","timestamp":1712102400000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T00:00:00Z","timestamp":1712102400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM068619"],"award-info":[{"award-number":["GM068619"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["2106031"],"award-info":[{"award-number":["2106031"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001824","name":"Czech Science Foundation","doi-asserted-by":"publisher","award":["GA19-20123S"],"award-info":[{"award-number":["GA19-20123S"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001824","name":"Czech Science Foundation","doi-asserted-by":"publisher","award":["GF21-26400K"],"award-info":[{"award-number":["GF21-26400K"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Education, Youth and Sports of the Czech Republic","award":["INTER-ACTION LUAUS23295"],"award-info":[{"award-number":["INTER-ACTION LUAUS23295"]}]},{"name":"Grant Agency of Masaryk University","award":["MUNI\/G\/1771\/2020"],"award-info":[{"award-number":["MUNI\/G\/1771\/2020"]}]},{"name":"National Institute for Cancer Research","award":["LX22NPO5102"],"award-info":[{"award-number":["LX22NPO5102"]}]},{"name":"Agency for Healthcare Research of the Czech Republic","award":["NU21-06-00512"],"award-info":[{"award-number":["NU21-06-00512"]}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>The differential signaling of multiple FGF ligands through a single fibroblast growth factor (FGF) receptor (FGFR) plays an important role in embryonic development. Here, we use quantitative biophysical tools to uncover the mechanism behind differences in FGFR1c signaling in response to FGF4, FGF8, and FGF9, a process which is relevant for limb bud outgrowth. We find that FGF8 preferentially induces FRS2 phosphorylation and extracellular matrix loss, while FGF4 and FGF9 preferentially induce FGFR1c phosphorylation and cell growth arrest. Thus, we demonstrate that FGF8 is a biased FGFR1c ligand, as compared to FGF4 and FGF9. F\u00f6rster resonance energy transfer experiments reveal a correlation between biased signaling and the conformation of the FGFR1c transmembrane domain dimer. Our findings expand the mechanistic understanding of FGF signaling during development and bring the poorly understood concept of receptor tyrosine kinase ligand bias into the spotlight.<\/jats:p>","DOI":"10.7554\/elife.88144","type":"journal-article","created":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T14:14:14Z","timestamp":1686060854000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.88144","source":"Crossref","is-referenced-by-count":1,"title":["Ligand bias underlies differential signaling of multiple FGFs via FGFR1"],"prefix":"10.7554","volume":"12","author":[{"given":"Kelly","family":"Karl","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Materials Science and Engineering, Institute for NanoBioTechnology, and Program in Molecular Biophysics, Johns Hopkins University","place":["Baltimore, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5104-7322","authenticated-orcid":true,"given":"Nuala","family":"Del Piccolo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Materials Science and Engineering, Institute for NanoBioTechnology, and Program in Molecular Biophysics, Johns Hopkins University","place":["Baltimore, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Taylor","family":"Light","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Materials Science and Engineering, Institute for NanoBioTechnology, and Program in Molecular Biophysics, Johns Hopkins University","place":["Baltimore, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0939-7158","authenticated-orcid":true,"given":"Tanaya","family":"Roy","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Materials Science and Engineering, Institute for NanoBioTechnology, and Program in Molecular Biophysics, Johns Hopkins University","place":["Baltimore, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Pooja","family":"Dudeja","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02j46qs45","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, Faculty of Medicine, Masaryk University","place":["Brno, Czech Republic"]},{"id":[{"id":"https:\/\/ror.org\/032h9wv69","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Animal Physiology and Genetics of the CAS","place":["Brno, Czech Republic"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Vlad-Constantin","family":"Ursachi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02j46qs45","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, Faculty of Medicine, Masaryk University","place":["Brno, Czech Republic"]},{"id":[{"id":"https:\/\/ror.org\/027v97282","id-type":"ROR","asserted-by":"publisher"}],"name":"International Clinical Research Center, St. Anne's University Hospital","place":["Brno, Czech Republic"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3869-7937","authenticated-orcid":true,"given":"Bohumil","family":"Fafilek","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02j46qs45","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, Faculty of Medicine, Masaryk University","place":["Brno, Czech Republic"]},{"id":[{"id":"https:\/\/ror.org\/032h9wv69","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Animal Physiology and Genetics of the CAS","place":["Brno, Czech Republic"]},{"id":[{"id":"https:\/\/ror.org\/027v97282","id-type":"ROR","asserted-by":"publisher"}],"name":"International Clinical Research Center, St. Anne's University Hospital","place":["Brno, Czech Republic"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0618-9134","authenticated-orcid":true,"given":"Pavel","family":"Krejci","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02j46qs45","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, Faculty of Medicine, Masaryk University","place":["Brno, Czech Republic"]},{"id":[{"id":"https:\/\/ror.org\/032h9wv69","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Animal Physiology and Genetics of the CAS","place":["Brno, Czech Republic"]},{"id":[{"id":"https:\/\/ror.org\/027v97282","id-type":"ROR","asserted-by":"publisher"}],"name":"International Clinical Research Center, St. Anne's University Hospital","place":["Brno, Czech Republic"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4274-4406","authenticated-orcid":true,"given":"Kalina","family":"Hristova","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Materials Science and Engineering, Institute for NanoBioTechnology, and Program in Molecular Biophysics, Johns Hopkins University","place":["Baltimore, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"4374","published-online":{"date-parts":[[2024,4,3]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.bpj.2020.11.2262","type":"journal-article","article-title":"The biased ligands NGF and NT-3 differentially stabilize Trk-A Dimers","volume":"120","author":"Ahmed","year":"2021","journal-title":"Biophysical Journal"},{"key":"bib2","volume-title":"Modern Business Statistics with Microsoft Excel","author":"Anderson","year":"2001","type":"book"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.bbamem.2016.10.024","type":"journal-article","article-title":"Helix-helix interactions in membrane domains of bitopic proteins: specificity and role of lipid environment","volume":"1859","author":"Bocharov","year":"2017","journal-title":"Biochimica et Biophysica Acta"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"419","DOI":"10.2174\/156800909788166484","type":"journal-article","article-title":"HER-2 signaling and inhibition in breast cancer","volume":"9","author":"Browne","year":"2009","journal-title":"Current Cancer Drug Targets"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"2445","DOI":"10.1007\/s00018-015-1856-8","type":"journal-article","article-title":"Instability restricts signaling of multiple fibroblast growth factors","volume":"72","author":"Buchtova","year":"2015","journal-title":"Cellular and Molecular Life Sciences"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"4018","DOI":"10.1074\/jbc.M107785200","type":"journal-article","article-title":"Association of the signaling adaptor FRS2 with fibroblast growth factor receptor 1 (Fgfr1) is mediated by alternative splicing of the juxtamembrane domain","volume":"277","author":"Burgar","year":"2002","journal-title":"The Journal of Biological Chemistry"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"3628","DOI":"10.1021\/ja910692u","type":"journal-article","article-title":"Measuring the energetics of membrane protein dimerization in mammalian membranes","volume":"132","author":"Chen","year":"2010","journal-title":"Journal of the American Chemical Society"},{"key":"bib8","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2001195","type":"journal-article","article-title":"The extracellular domain of fibroblast growth factor receptor 3 inhibits ligand-independent dimerization","volume":"3","author":"Chen","year":"2010","journal-title":"Science Signaling"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"6887","DOI":"10.1021\/jm401677g","type":"journal-article","article-title":"Biased ligand modulation of seven transmembrane receptors (7TMRs): functional implications for drug discovery","volume":"57","author":"Correll","year":"2014","journal-title":"Journal of Medicinal Chemistry"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1083\/jcb.200302075","type":"journal-article","article-title":"A network of transcriptional and signaling events is activated by FGF to induce chondrocyte growth arrest and differentiation","volume":"161","author":"Dailey","year":"2003","journal-title":"The Journal of Cell Biology"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"8650","DOI":"10.1021\/ac301776j","type":"journal-article","article-title":"Production of plasma membrane vesicles with chloride salts and their utility as a cell membrane mimetic for biophysical characterization of membrane protein interactions","volume":"84","author":"Del Piccolo","year":"2012","journal-title":"Analytical Chemistry"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1002\/bies.201100118","type":"journal-article","article-title":"Scanning image correlation spectroscopy","volume":"34","author":"Digman","year":"2012","journal-title":"BioEssays"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1016\/j.chembiol.2015.05.008","type":"journal-article","article-title":"Growth factor identity is encoded by discrete coiled-coil rotamers in the EGFR Juxtamembrane region","volume":"22","author":"Doerner","year":"2015","journal-title":"Chemistry & Biology"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/bs.pmbts.2018.08.001","type":"journal-article","article-title":"Analysis of biased agonism","volume":"160","author":"Ehlert","year":"2018","journal-title":"Progress in Molecular Biology and Translational Science"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.cytogfr.2005.01.001","type":"journal-article","article-title":"Cellular signaling by fibroblast growth factor receptors","volume":"16","author":"Eswarakumar","year":"2005","journal-title":"Cytokine & Growth Factor Reviews"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"1522","DOI":"10.1016\/j.joca.2017.05.014","type":"journal-article","article-title":"Statins do not inhibit the FGFR signaling in chondrocytes","volume":"25","author":"Fafilek","year":"2017","journal-title":"Osteoarthritis and Cartilage"},{"key":"bib17","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aap8608","type":"journal-article","article-title":"The inositol phosphatase SHIP2 enables sustained ERK activation downstream of FGF receptors by recruiting Src kinases","volume":"11","author":"Fafilek","year":"2018","journal-title":"Science Signaling"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1016\/j.cell.2017.09.017","type":"journal-article","article-title":"EGFR ligands differentially stabilize receptor dimers to specify signaling kinetics","volume":"171","author":"Freed","year":"2017","journal-title":"Cell"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1016\/j.molcel.2006.01.022","type":"journal-article","article-title":"Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction","volume":"21","author":"Furdui","year":"2006","journal-title":"Molecular Cell"},{"key":"bib20","first-page":"47","type":"journal-article","article-title":"Basic fibroblast growth factor (FGF-2) internalization through the heparan sulfate proteoglycans-mediated pathway: an ultrastructural approach","volume":"66","author":"Gleizes","year":"1995","journal-title":"European Journal of Cell Biology"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1038\/nrm3528","type":"journal-article","article-title":"Exploring mechanisms of FGF signalling through the lens of structural biology","volume":"14","author":"Goetz","year":"2013","journal-title":"Nature Reviews Molecular Cell Biology"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"8791","DOI":"10.1074\/jbc.RA119.008213","type":"journal-article","article-title":"Engineering nanomolar peptide ligands that differentially modulate EphA2 receptor signaling","volume":"294","author":"Gomez-Soler","year":"2019","journal-title":"The Journal of Biological Chemistry"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.1111\/j.1349-7006.2008.00840.x","type":"journal-article","article-title":"Regulation of growth factor signaling by FRS2 family docking\/scaffold adaptor proteins","volume":"99","author":"Gotoh","year":"2008","journal-title":"Cancer Science"},{"key":"bib24","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.21536","type":"journal-article","article-title":"One reporter for in-cell activity profiling of majority of protein kinase oncogenes","volume":"6","author":"Gudernova","year":"2017","journal-title":"eLife"},{"key":"bib25","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2017.00017","type":"journal-article","article-title":"A practical guide to approaching biased agonism at g protein coupled receptors","volume":"11","author":"Gundry","year":"2017","journal-title":"Frontiers in Neuroscience"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"3966","DOI":"10.1128\/MCB.18.7.3966","type":"journal-article","article-title":"Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation","volume":"18","author":"Hadari","year":"1998","journal-title":"Molecular and Cellular Biology"},{"key":"bib27","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.14107","type":"journal-article","article-title":"Molecular basis for multimerization in the activation of the epidermal growth factor receptor","volume":"5","author":"Huang","year":"2016","journal-title":"eLife"},{"key":"bib28","volume-title":"Measurements and their uncertainties: a practical guide to modern error analysis","author":"Hughes","year":"2010","type":"book"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1038\/nchembio.634","type":"journal-article","article-title":"Multiple ligand-specific conformations of the \u03b22-adrenergic receptor","volume":"7","author":"Kahsai","year":"2011","journal-title":"Nature Chemical Biology"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.bbrc.2017.01.001","type":"journal-article","article-title":"Type II cGMP-dependent protein kinase negatively regulates fibroblast growth factor signaling by phosphorylating Raf-1 at serine 43 in rat chondrosarcoma cells","volume":"483","author":"Kamemura","year":"2017","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"18494","DOI":"10.1074\/jbc.REV120.015190","type":"journal-article","article-title":"Ligand bias in receptor tyrosine kinase signaling","volume":"295","author":"Karl","year":"2020","journal-title":"The Journal of Biological Chemistry"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.sbi.2021.07.003","type":"journal-article","article-title":"Pondering the mechanism of receptor tyrosine kinase activation: The case for ligand-specific dimer microstate ensembles","volume":"71","author":"Karl","year":"2021","journal-title":"Current Opinion in Structural Biology"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1124\/jpet.110.173948","type":"journal-article","article-title":"Functional selectivity and biased receptor signaling","volume":"336","author":"Kenakin","year":"2011","journal-title":"The Journal of Pharmacology and Experimental Therapeutics"},{"key":"bib34","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3954-c2","type":"journal-article","article-title":"Measurements of ligand bias and functional affinity","volume":"12","author":"Kenakin","year":"2013","journal-title":"Nature Reviews. Drug Discovery"},{"key":"bib35","doi-asserted-by":"publisher","DOI":"10.1002\/cpph.11","type":"journal-article","article-title":"Measurement of receptor signaling bias","volume":"74","author":"Kenakin","year":"2016","journal-title":"Current Protocols in Pharmacology"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1124\/pr.118.016790","type":"journal-article","article-title":"Biased receptor signaling in drug discovery","volume":"71","author":"Kenakin","year":"2019","journal-title":"Pharmacological Reviews"},{"key":"bib37","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aba4226","type":"journal-article","article-title":"An RNA aptamer restores defective bone growth in FGFR3-related skeletal dysplasia in mice","volume":"13","author":"Kimura","year":"2021","journal-title":"Science Translational Medicine"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1039\/c5ib00202h","type":"journal-article","article-title":"Fully quantified spectral imaging reveals in vivo membrane protein interactions","volume":"8","author":"King","year":"2016","journal-title":"Integrative Biology"},{"key":"bib39","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaz5267","type":"journal-article","article-title":"Kinetics of receptor tyrosine kinase activation define ERK signaling dynamics","volume":"13","author":"Kiyatkin","year":"2020","journal-title":"Science Signaling"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"2865","DOI":"10.1128\/MCB.01730-12","type":"journal-article","article-title":"The B55\u03b1 regulatory subunit of protein phosphatase 2A mediates fibroblast growth factor-induced p107 dephosphorylation and growth arrest in chondrocytes","volume":"33","author":"Kolupaeva","year":"2013","journal-title":"Molecular and Cellular Biology"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.bone.2010.03.021","type":"journal-article","article-title":"FGFR3 signaling induces a reversible senescence phenotype in chondrocytes similar to oncogene-induced premature senescence","volume":"47","author":"Krejci","year":"2010","journal-title":"Bone"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1146\/annurev-biophys-051013-022942","type":"journal-article","article-title":"What Do Structures Tell Us About Chemokine Receptor Function and Antagonism?","volume":"46","author":"Kufareva","year":"2017","journal-title":"Annual Review of Biophysics"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/bs.acr.2020.04.001","type":"journal-article","article-title":"HER family in cancer progression: From discovery to 2020 and beyond","volume":"147","author":"Kumar","year":"2020","journal-title":"Advances in Cancer Research"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/s1097-2765(02)00689-5","type":"journal-article","article-title":"The docking protein FRS2alpha controls a MAP kinase-mediated negative feedback mechanism for signaling by FGF receptors","volume":"10","author":"Lax","year":"2002","journal-title":"Molecular Cell"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/j.jtho.2020.10.006","type":"journal-article","article-title":"Dual EGFR-VEGF pathway inhibition: a promising strategy for patients with EGFR-Mutant NSCLC","volume":"16","author":"Le","year":"2021","journal-title":"Journal of Thoracic Oncology"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1016\/j.cell.2010.06.011","type":"journal-article","article-title":"Cell signaling by receptor tyrosine kinases","volume":"141","author":"Lemmon","year":"2010","journal-title":"Cell"},{"key":"bib47","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2000021","type":"journal-article","article-title":"The precise sequence of FGF receptor autophosphorylation is kinetically driven and is disrupted by oncogenic mutations","volume":"2","author":"Lew","year":"2009","journal-title":"Science Signaling"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"6241","DOI":"10.1021\/bi060609y","type":"journal-article","article-title":"Role of receptor tyrosine kinase transmembrane domains in cell signaling and human pathologies","volume":"45","author":"Li","year":"2006","journal-title":"Biochemistry"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1126\/science.1215802","type":"journal-article","article-title":"Biased signaling pathways in \u03b22-adrenergic receptor characterized by 19F-NMR","volume":"335","author":"Liu","year":"2012","journal-title":"Science"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"5432","DOI":"10.1128\/MCB.00742-10","type":"journal-article","article-title":"Structural evidence for loose linkage between ligand binding and kinase activation in the epidermal growth factor receptor","volume":"30","author":"Lu","year":"2010","journal-title":"Molecular and Cellular Biology"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1210\/me.2013-1314","type":"journal-article","article-title":"Minireview: more than just a hammer: ligand \u201cbias\u201d and pharmaceutical discovery","volume":"28","author":"Luttrell","year":"2014","journal-title":"Molecular Endocrinology"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1038\/nature01655","type":"journal-article","article-title":"Deciphering skeletal patterning: clues from the limb","volume":"423","author":"Mariani","year":"2003","journal-title":"Nature"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1038\/nature06876","type":"journal-article","article-title":"Genetic evidence that FGFs have an instructive role in limb proximal-distal patterning","volume":"453","author":"Mariani","year":"2008","journal-title":"Nature"},{"key":"bib54","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0081569","type":"journal-article","article-title":"Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia","volume":"8","author":"Matsushita","year":"2013","journal-title":"PLOS ONE"},{"key":"bib55","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.cytogfr.2005.01.008","type":"journal-article","article-title":"Structural basis for fibroblast growth factor receptor activation","volume":"16","author":"Mohammadi","year":"2005","journal-title":"Cytokine & Growth Factor Reviews"},{"key":"bib56","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1002\/jcp.1041310118","type":"journal-article","article-title":"High and low affinity binding sites for basic fibroblast growth factor on cultured cells: absence of A role for low affinity binding in the stimulation of plasminogen activator production by bovine capillary endothelial cells","volume":"131","author":"Moscatelli","year":"1987","journal-title":"Journal of Cellular Physiology"},{"key":"bib57","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13307","type":"journal-article","article-title":"EGFR oligomerization organizes kinase-active dimers into competent signalling platforms","volume":"7","author":"Needham","year":"2016","journal-title":"Nature Communications"},{"key":"bib58","doi-asserted-by":"publisher","first-page":"360","DOI":"10.4161\/19336918.2014.971684","type":"journal-article","article-title":"Homotypic receptor-receptor interactions regulating Eph signaling","volume":"8","author":"Nikolov","year":"2014","journal-title":"Cell Adhesion & Migration"},{"key":"bib59","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1128\/MCB.20.3.979-989.2000","type":"journal-article","article-title":"FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors","volume":"20","author":"Ong","year":"2000","journal-title":"Molecular and Cellular Biology"},{"key":"bib60","doi-asserted-by":"publisher","first-page":"15292","DOI":"10.1074\/jbc.271.25.15292","type":"journal-article","article-title":"Receptor specificity of the fibroblast growth factor family","volume":"271","author":"Ornitz","year":"1996","journal-title":"The Journal of Biological Chemistry"},{"key":"bib61","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2001-2-3-reviews3005","type":"journal-article","article-title":"Fibroblast growth factors","volume":"2","author":"Ornitz","year":"2001","journal-title":"Genome Biology"},{"key":"bib62","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1002\/(SICI)1096-8628(19980707)78:3<237::AID-AJMG5>3.0.CO;2-M","type":"journal-article","article-title":"Description of a new mutation and characterization of FGFR1, FGFR2, and FGFR3 mutations among Brazilian patients with syndromic craniosynostoses","volume":"78","author":"Passos-Bueno","year":"1998","journal-title":"American Journal of Medical Genetics"},{"key":"bib63","doi-asserted-by":"publisher","first-page":"5881","DOI":"10.1021\/acs.chemrev.8b00467","type":"journal-article","article-title":"The RTK interactome: overview and perspective on RTK heterointeractions","volume":"119","author":"Paul","year":"2019","journal-title":"Chemical Reviews"},{"key":"bib64","doi-asserted-by":"publisher","first-page":"9917","DOI":"10.1074\/jbc.RA120.013639","type":"journal-article","article-title":"Quantifying the strength of heterointeractions among receptor tyrosine kinases from different subfamilies: implications for cell signaling","volume":"295","author":"Paul","year":"2020","journal-title":"Journal of Biological Chemistry"},{"key":"bib65","doi-asserted-by":"publisher","first-page":"6503","DOI":"10.1002\/anie.202010049","type":"journal-article","article-title":"Probing membrane protein association using concentration-dependent number and brightness","volume":"60","author":"Paul","year":"2021","journal-title":"Angewandte Chemie"},{"key":"bib66","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1002\/jcp.20620","type":"journal-article","article-title":"Downregulation of Akt activity contributes to the growth arrest induced by FGF in chondrocytes","volume":"207","author":"Priore","year":"2006","journal-title":"Journal of Cellular Physiology"},{"key":"bib67","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1124\/mol.111.072801","type":"journal-article","article-title":"Quantifying ligand bias at seven-transmembrane receptors","volume":"80","author":"Rajagopal","year":"2011","journal-title":"Molecular Pharmacology"},{"key":"bib68","doi-asserted-by":"publisher","first-page":"1747","DOI":"10.1074\/jbc.M310384200","type":"journal-article","article-title":"Activation of the ERK1\/2 and p38 mitogen-activated protein kinase pathways mediates fibroblast growth factor-induced growth arrest of chondrocytes","volume":"279","author":"Raucci","year":"2004","journal-title":"The Journal of Biological Chemistry"},{"key":"bib69","doi-asserted-by":"publisher","first-page":"3036","DOI":"10.1016\/S0006-3495(00)76842-1","type":"journal-article","article-title":"Endocytosis switch controlled by transmembrane osmotic pressure and phospholipid number asymmetry","volume":"78","author":"Rauch","year":"2000","journal-title":"Biophysical Journal"},{"key":"bib70","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/s0168-9525(00)02021-7","type":"journal-article","article-title":"RTK mutations and human syndromeswhen good receptors turn bad","volume":"16","author":"Robertson","year":"2000","journal-title":"Trends in Genetics"},{"key":"bib71","doi-asserted-by":"crossref","first-page":"3976","DOI":"10.1016\/S0021-9258(17)41730-3","type":"journal-article","article-title":"Heparin increases the affinity of basic fibroblast growth factor for its receptor but is not required for binding","volume":"269","author":"Roghani","year":"1994","journal-title":"The Journal of Biological Chemistry"},{"key":"bib72","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1242\/jcs.115.3.553","type":"journal-article","article-title":"Induction of chondrocyte growth arrest by FGF: transcriptional and cytoskeletal alterations","volume":"115","author":"Rozenblatt-Rosen","year":"2002","journal-title":"Journal of Cell Science"},{"key":"bib73","doi-asserted-by":"publisher","first-page":"2262","DOI":"10.1021\/acs.accounts.5b00238","type":"journal-article","article-title":"Characterization of membrane protein interactions in plasma membrane derived vesicles with quantitative imaging f\u00f6rster resonance energy transfer","volume":"48","author":"Sarabipour","year":"2015","journal-title":"Accounts of Chemical Research"},{"key":"bib74","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.13876","type":"journal-article","article-title":"VEGFR-2 conformational switch in response to ligand binding","volume":"5","author":"Sarabipour","year":"2016","journal-title":"eLife"},{"key":"bib75","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10262","type":"journal-article","article-title":"Mechanism of FGF receptor dimerization and activation","volume":"7","author":"Sarabipour","year":"2016","journal-title":"Nature Communications"},{"key":"bib76","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1021\/cb300216f","type":"journal-article","article-title":"Bipartite tetracysteine display reveals allosteric control of ligand-specific EGFR activation","volume":"7","author":"Scheck","year":"2012","journal-title":"ACS Chemical Biology"},{"key":"bib77","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/S0092-8674(00)00114-8","type":"journal-article","article-title":"Cell Signaling by receptor tyrosine kinases","volume":"103","author":"Schlessinger","year":"2000","journal-title":"Cell"},{"key":"bib78","doi-asserted-by":"publisher","first-page":"1506","DOI":"10.1126\/science.1105396","type":"journal-article","article-title":"Common and distinct elements in cellular signaling via EGF and FGF receptors","volume":"306","author":"Schlessinger","year":"2004","journal-title":"Science"},{"key":"bib79","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1038\/nsmb.1782","type":"journal-article","article-title":"An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly","volume":"17","author":"Seiradake","year":"2010","journal-title":"Nature Structural & Molecular Biology"},{"key":"bib80","doi-asserted-by":"publisher","first-page":"958","DOI":"10.1038\/nsmb.2617","type":"journal-article","article-title":"Structurally encoded intraclass differences in EphA clusters drive distinct cell responses","volume":"20","author":"Seiradake","year":"2013","journal-title":"Nature Structural & Molecular Biology"},{"key":"bib81","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1007\/s00428-014-1634-2","type":"journal-article","article-title":"FGFR1 amplification is associated with poor prognosis and smoking in non-small-cell lung cancer","volume":"465","author":"Seo","year":"2014","journal-title":"Virchows Archiv"},{"key":"bib82","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-018-0017-7","type":"journal-article","article-title":"The EphA2 receptor is activated through induction of distinct, ligand-dependent oligomeric structures","volume":"1","author":"Singh","year":"2018","journal-title":"Communications Biology"},{"key":"bib83","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1016\/j.cell.2010.12.031","type":"journal-article","article-title":"Cells respond to mechanical stress by rapid disassembly of caveolae","volume":"144","author":"Sinha","year":"2011","journal-title":"Cell"},{"key":"bib84","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1038\/nrd.2017.229","type":"journal-article","article-title":"Biased signalling: from simple switches to allosteric microprocessors","volume":"17","author":"Smith","year":"2018","journal-title":"Nature Reviews. Drug Discovery"},{"key":"bib85","doi-asserted-by":"crossref","first-page":"17056","DOI":"10.1016\/S0021-9258(17)32519-X","type":"journal-article","article-title":"Internalization of fibroblast growth factor receptor is inhibited by a point mutation at tyrosine 766","volume":"269","author":"Sorokin","year":"1994","journal-title":"The Journal of Biological Chemistry"},{"key":"bib86","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41592-019-0408-9","type":"journal-article","article-title":"A general method to quantify ligand-driven oligomerization from fluorescence-based images","volume":"16","author":"Stoneman","year":"2019","journal-title":"Nature Methods"},{"key":"bib87","doi-asserted-by":"publisher","DOI":"10.1098\/rsif.2013.0742","type":"journal-article","article-title":"Biphasic responses in multi-site phosphorylation systems","volume":"10","author":"Suwanmajo","year":"2013","journal-title":"Journal of the Royal Society, Interface"},{"key":"bib88","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1101\/gad.1547407","type":"journal-article","article-title":"Rethinking the proximodistal axis of the vertebrate limb in the molecular era","volume":"21","author":"Tabin","year":"2007","journal-title":"Genes & Development"},{"key":"bib89","doi-asserted-by":"publisher","first-page":"4613","DOI":"10.1158\/0008-5472.CAN-08-2816","type":"journal-article","article-title":"Fibroblast growth factor receptor 1 promotes proliferation and survival via activation of the mitogen-activated protein kinase pathway in bladder cancer","volume":"69","author":"Tomlinson","year":"2009","journal-title":"Cancer Research"},{"key":"bib90","doi-asserted-by":"publisher","first-page":"2085","DOI":"10.1158\/0008-5472.CAN-09-3746","type":"journal-article","article-title":"FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer","volume":"70","author":"Turner","year":"2010","journal-title":"Cancer Research"},{"key":"bib91","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1126\/science.1232808","type":"journal-article","article-title":"Structural features for functional selectivity at serotonin receptors","volume":"340","author":"Wacker","year":"2013","journal-title":"Science"},{"key":"bib92","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1124\/jpet.114.218560","type":"journal-article","article-title":"Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism","volume":"353","author":"Wendt","year":"2015","journal-title":"The Journal of Pharmacology and Experimental Therapeutics"},{"key":"bib93","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1086\/427956","type":"journal-article","article-title":"Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation","volume":"76","author":"White","year":"2005","journal-title":"American Journal of Human Genetics"},{"key":"bib94","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.cytogfr.2005.03.001","type":"journal-article","article-title":"Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations","volume":"16","author":"Wilkie","year":"2005","journal-title":"Cytokine & Growth Factor Reviews"},{"key":"bib95","doi-asserted-by":"publisher","first-page":"7260","DOI":"10.1038\/onc.2008.328","type":"journal-article","article-title":"Soluble monomeric EphrinA1 is released from tumor cells and is a functional ligand for the EphA2 receptor","volume":"27","author":"Wykosky","year":"2008","journal-title":"Oncogene"},{"key":"bib96","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1210\/me.2006-0518","type":"journal-article","article-title":"Distinct roles of fibroblast growth factor receptor 1 and 2 in regulating cell survival and epithelial-mesenchymal transition","volume":"21","author":"Xian","year":"2007","journal-title":"Molecular Endocrinology"},{"key":"bib97","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-00222-7","type":"journal-article","article-title":"FGF\/FGFR signaling in health and disease","volume":"5","author":"Xie","year":"2020","journal-title":"Signal Transduction and Targeted Therapy"},{"key":"bib98","doi-asserted-by":"publisher","first-page":"1821","DOI":"10.1007\/s00586-015-4367-2","type":"journal-article","article-title":"A proposed classification system for guiding surgical strategy in cases of severe spinal deformity based on spinal cord function","volume":"25","author":"Yang","year":"2016","journal-title":"European Spine Journal"},{"key":"bib99","doi-asserted-by":"publisher","first-page":"15694","DOI":"10.1074\/jbc.M601252200","type":"journal-article","article-title":"Receptor specificity of the fibroblast growth factor family: the complete mammalian FGF family","volume":"281","author":"Zhang","year":"2006","journal-title":"The Journal of Biological Chemistry"},{"key":"bib100","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1016\/j.immuni.2017.05.002","type":"journal-article","article-title":"Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV","volume":"46","author":"Zheng","year":"2017","journal-title":"Immunity"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/88144\/elife-88144-v2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/88144\/elife-88144-v2.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/88144","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T10:33:57Z","timestamp":1787567637000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/88144"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,3]]},"references-count":100,"alternative-id":["10.7554\/eLife.88144"],"URL":"https:\/\/doi.org\/10.7554\/elife.88144","archive":["CLOCKSS"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.01.06.475273","asserted-by":"subject"},{"id-type":"doi","id":"10.1101\/2022.01.06.475273","asserted-by":"object"}],"is-same-as":[{"id-type":"doi","id":"10.7554\/eLife.88144.4","asserted-by":"subject"}],"is-version-of":[{"id-type":"doi","id":"10.7554\/eLife.88144.1","asserted-by":"subject"},{"id-type":"doi","id":"10.7554\/eLife.88144.2","asserted-by":"subject"},{"id-type":"doi","id":"10.7554\/eLife.88144.3","asserted-by":"subject"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,3]]},"assertion":[{"value":"single anonymised","name":"peer_review_transparency","label":"Peer review transparency","group":{"name":"peer_review_taxonomy"}},{"value":"other reviewer(s), editor","name":"peer_review_interaction","label":"Peer review interaction","group":{"name":"peer_review_taxonomy"}},{"value":"review summaries, review reports, author\/editor communication, reviewer identities reviewer opt in, editor identities","name":"peer_review_published","label":"Peer review published","group":{"name":"peer_review_taxonomy"}},{"value":"open (sign in with ORCID iD required)","name":"post_publication_commenting","label":"Post publication commenting","group":{"name":"post_publication_commenting"}}],"article-number":"RP88144"}}