{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T07:04:39Z","timestamp":1780383879977,"version":"3.54.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1013254","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000}}],"reference-count":79,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T00:00:00Z","timestamp":1752624000000},"content-version":"vor","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":["R01-GM129074"],"award-info":[{"award-number":["R01-GM129074"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01-HL101200"],"award-info":[{"award-number":["R01-HL101200"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R35-HL139950"],"award-info":[{"award-number":["R35-HL139950"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    The vascular endothelial growth factor receptors (VEGFRs) bind to cognate ligands to facilitate signaling pathways critical for angiogenesis, the growth of new capillaries from existing vasculature. Intracellular trafficking regulates the availability of receptors on the cell surface to bind ligands, which regulate activation, and the movement of activated receptors between the surface and intracellular pools, where they can initiate different signaling pathways. Using experimental data and computational modeling, we recently demonstrated and quantified the differential trafficking of three VEGF receptors, VEGFR1, VEGFR2, and coreceptor Neuropilin-1 (NRP1). Here, we expand that approach to quantify how the binding of different VEGF ligands alters the trafficking of these VEGF receptors and demonstrate the consequences of receptor localization and ligand binding on the localization and dynamics of signal initiation complexes. We include simulations of four different splice isoforms of VEGF-A and PLGF, each of which binds to different combinations of the VEGF receptors, and we use new experimental data for two of these ligands to parameterize and validate our model. We show that VEGFR2 trafficking is altered in response to ligand binding, but that trafficking of VEGFR1 is not; we also show that the altered trafficking can be explained by a single mechanistic process, increased internalization of the VEGFR2 receptor when bound to ligand; other processes are unaffected. We further show that even though the canonical view of receptor tyrosine kinases is of activation on the cell surface, most of the ligand-receptor complexes for both VEGFR1 and VEGFR2 are intracellular. We also explore the competition between the receptors for ligand binding, the so-called \u2018decoy effect\u2019, and show that while\n                    <jats:italic>in vitro<\/jats:italic>\n                    on the cell surface minimal such effect would be observed, inside the cell the effect can be substantial and may influence signaling. We term this location dependence the \u2018reservoir effect\u2019 as the size of the local ligand reservoir (large outside the cell, small inside the cell) plays an integral role in the receptor-receptor competition. These results expand our understanding of receptor-ligand trafficking dynamics and are critical for the design of therapeutic agents to regulate ligand availability to VEGFR1 and hence VEGF receptor signaling in angiogenesis.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1013254","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T17:42:22Z","timestamp":1752687742000},"page":"e1013254","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Impact of ligand binding on VEGFR1, VEGFR2, and NRP1 localization in human endothelial cells"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5097-5509","authenticated-orcid":true,"given":"Sarvenaz","family":"Sarabipour","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2736-220X","authenticated-orcid":true,"given":"Karina","family":"Kinghorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitlyn M.","family":"Quigley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Kovacs-Kasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6538-8243","authenticated-orcid":true,"given":"Brian H.","family":"Annex","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2135-5153","authenticated-orcid":true,"given":"Victoria L.","family":"Bautch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3481-7740","authenticated-orcid":true,"given":"Feilim","family":"Mac Gabhann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,7,16]]},"reference":[{"issue":"9","key":"pcbi.1013254.ref001","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a006452","article-title":"VEGF-directed blood vessel patterning: from cells to organism","volume":"2","author":"VL Bautch","year":"2012","journal-title":"Cold Spring Harb Perspect Med"},{"issue":"4","key":"pcbi.1013254.ref002","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/74651","article-title":"Mechanisms of angiogenesis and arteriogenesis","volume":"6","author":"P Carmeliet","year":"2000","journal-title":"Nat Med"},{"issue":"9","key":"pcbi.1013254.ref003","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a009183","article-title":"Receptor tyrosine kinase-mediated angiogenesis","volume":"5","author":"M Jeltsch","year":"2013","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"7","key":"pcbi.1013254.ref004","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/nrcardio.2013.70","article-title":"Therapeutic angiogenesis for critical limb ischaemia","volume":"10","author":"BH Annex","year":"2013","journal-title":"Nat Rev Cardiol"},{"issue":"12","key":"pcbi.1013254.ref005","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1161\/CIRCRESAHA.121.318266","article-title":"New Directions in Therapeutic Angiogenesis and Arteriogenesis in Peripheral Arterial Disease","volume":"128","author":"BH Annex","year":"2021","journal-title":"Circ Res"},{"issue":"12","key":"pcbi.1013254.ref006","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1002\/psp4.12261","article-title":"Systems Pharmacology of VEGF165b in Peripheral Artery Disease","volume":"6","author":"LE Clegg","year":"2017","journal-title":"CPT Pharmacomet Syst Pharmacol"},{"key":"pcbi.1013254.ref007","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.13876","article-title":"VEGFR-2 conformational switch in response to ligand binding","volume":"5","author":"S Sarabipour","year":"2016","journal-title":"Elife"},{"issue":"13","key":"pcbi.1013254.ref008","doi-asserted-by":"crossref","first-page":"108187","DOI":"10.1016\/j.celrep.2020.108187","article-title":"Heterogeneity in VEGF Receptor-2 Mobility and Organization on the Endothelial Cell Surface Leads to Diverse Models of Activation by VEGF","volume":"32","author":"B da Rocha-Azevedo","year":"2020","journal-title":"Cell Rep"},{"issue":"37","key":"pcbi.1013254.ref009","doi-asserted-by":"crossref","first-page":"25110","DOI":"10.1074\/jbc.C800137200","article-title":"Neuropilin-1-VEGFR-2 complexing requires the PDZ-binding domain of neuropilin-1","volume":"283","author":"C Prahst","year":"2008","journal-title":"J Biol Chem"},{"issue":"10","key":"pcbi.1013254.ref010","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/nrm.2016.87","article-title":"Mechanisms and regulation of endothelial VEGF receptor signalling","volume":"17","author":"M Simons","year":"2016","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"6","key":"pcbi.1013254.ref011","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/s12276-022-00785-1","article-title":"Flow goes forward and cells step backward: endothelial migration","volume":"54","author":"H-W Lee","year":"2022","journal-title":"Exp Mol Med"},{"issue":"8","key":"pcbi.1013254.ref012","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a011056","article-title":"PlGF: a multitasking cytokine with disease-restricted activity","volume":"2","author":"M Dewerchin","year":"2012","journal-title":"Cold Spring Harb Perspect Med"},{"issue":"2","key":"pcbi.1013254.ref013","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.str.2016.12.012","article-title":"Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A","volume":"25","author":"S Markovic-Mueller","year":"2017","journal-title":"Structure"},{"issue":"3","key":"pcbi.1013254.ref014","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1182\/blood-2011-01-328773","article-title":"Neuropilin-1 promotes VEGFR-2 trafficking through Rab11 vesicles thereby specifying signal output","volume":"118","author":"K Ballmer-Hofer","year":"2011","journal-title":"Blood"},{"key":"pcbi.1013254.ref015","doi-asserted-by":"crossref","first-page":"3487","DOI":"10.1242\/jcs.016410","article-title":"Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors","volume":"121","author":"DG Nowak","year":"2008","journal-title":"J Cell Sci"},{"issue":"18","key":"pcbi.1013254.ref016","doi-asserted-by":"crossref","first-page":"6886","DOI":"10.1073\/pnas.1201626109","article-title":"Tissue deformation spatially modulates VEGF signaling and angiogenesis","volume":"109","author":"NC Rivron","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"20","key":"pcbi.1013254.ref017","doi-asserted-by":"crossref","first-page":"2684","DOI":"10.1101\/gad.242002","article-title":"Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis","volume":"16","author":"C Ruhrberg","year":"2002","journal-title":"Genes Dev"},{"issue":"49","key":"pcbi.1013254.ref018","doi-asserted-by":"crossref","first-page":"35172","DOI":"10.1074\/jbc.274.49.35172","article-title":"Placenta growth factor and vascular endothelial growth factor B and C expression in microvascular endothelial cells and pericytes. Implication in autocrine and paracrine regulation of angiogenesis","volume":"274","author":"H Yonekura","year":"1999","journal-title":"J Biol Chem"},{"key":"pcbi.1013254.ref019","first-page":"31","article-title":"Structure, expression and receptor-binding properties of placenta growth factor (PlGF)","volume":"237","author":"MG Persico","year":"1999","journal-title":"Curr Top Microbiol Immunol"},{"issue":"1","key":"pcbi.1013254.ref020","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cytogfr.2013.11.002","article-title":"Extracellular regulation of VEGF: isoforms, proteolysis, and vascular patterning","volume":"25","author":"P Vempati","year":"2014","journal-title":"Cytokine Growth Factor Rev"},{"issue":"2","key":"pcbi.1013254.ref021","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1002\/1097-0177(2000)9999:9999<::AID-DVDY1093>3.0.CO;2-D","article-title":"Differential expression of VEGF isoforms in mouse during development and in the adult","volume":"220","author":"YS Ng","year":"2001","journal-title":"Dev Dyn"},{"issue":"19","key":"pcbi.1013254.ref022","doi-asserted-by":"crossref","first-page":"7282","DOI":"10.1128\/MCB.20.19.7282-7291.2000","article-title":"Isoforms of vascular endothelial growth factor act in a coordinate fashion to recruit and expand tumor vasculature","volume":"20","author":"J Grunstein","year":"2000","journal-title":"Mol Cell Biol"},{"issue":"4","key":"pcbi.1013254.ref023","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1083\/jcb.200409115","article-title":"Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors","volume":"169","author":"S Lee","year":"2005","journal-title":"J Cell Biol"},{"issue":"4","key":"pcbi.1013254.ref024","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1182\/blood-2002-11-3423","article-title":"Mechanism of monocyte activation and expression of proinflammatory cytochemokines by placenta growth factor","volume":"102","author":"SK Selvaraj","year":"2003","journal-title":"Blood"},{"issue":"34","key":"pcbi.1013254.ref025","doi-asserted-by":"crossref","first-page":"13932","DOI":"10.1073\/pnas.1309629110","article-title":"Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth","volume":"110","author":"X Yang","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"pcbi.1013254.ref026","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/87904","article-title":"Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions","volume":"7","author":"P Carmeliet","year":"2001","journal-title":"Nat Med"},{"issue":"3","key":"pcbi.1013254.ref027","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s10456-004-4179-1","article-title":"Placenta growth factor is not required for exercise-induced angiogenesis","volume":"7","author":"B Gigante","year":"2004","journal-title":"Angiogenesis"},{"issue":"1","key":"pcbi.1013254.ref028","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.cell.2010.01.033","article-title":"PlGF Blockade Does Not Inhibit Angiogenesis during Primary Tumor Growth","volume":"141","author":"C Bais","year":"2010","journal-title":"Cell"},{"issue":"5","key":"pcbi.1013254.ref029","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1111\/micc.12113","article-title":"Placenta growth factor and vascular endothelial growth factor a have differential, cell-type specific patterns of expression in vascular cells","volume":"21","author":"L Xiang","year":"2014","journal-title":"Microcirculation"},{"issue":"5","key":"pcbi.1013254.ref030","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1242\/dev.145672","article-title":"Blood vessel anastomosis is spatially regulated by Flt1 during angiogenesis","volume":"144","author":"JE Nesmith","year":"2017","journal-title":"Development"},{"issue":"5","key":"pcbi.1013254.ref031","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1083\/jcb.200709114","article-title":"The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching","volume":"181","author":"NC Kappas","year":"2008","journal-title":"J Cell Biol"},{"issue":"16","key":"pcbi.1013254.ref032","doi-asserted-by":"crossref","first-page":"9349","DOI":"10.1073\/pnas.95.16.9349","article-title":"Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice","volume":"95","author":"S Hiratsuka","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7","key":"pcbi.1013254.ref033","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1038\/nm884","article-title":"Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1","volume":"9","author":"M Autiero","year":"2003","journal-title":"Nat Med"},{"issue":"1","key":"pcbi.1013254.ref034","doi-asserted-by":"crossref","DOI":"10.1152\/ajpheart.00254.2003","article-title":"Model of competitive binding of vascular endothelial growth factor and placental growth factor to VEGF receptors on endothelial cells","volume":"286","author":"F Mac Gabhann","year":"2004","journal-title":"Am J Physiol-Heart Circ Physiol"},{"issue":"1","key":"pcbi.1013254.ref035","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/j.1600-0854.2009.01001.x","article-title":"Ligand-stimulated VEGFR2 signaling is regulated by co-ordinated trafficking and proteolysis","volume":"11","author":"AF Bruns","year":"2010","journal-title":"Traffic"},{"issue":"11","key":"pcbi.1013254.ref036","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0048539","article-title":"A heat-shock protein axis regulates VEGFR2 proteolysis, blood vessel development and repair","volume":"7","author":"AF Bruns","year":"2012","journal-title":"PLoS ONE"},{"key":"pcbi.1013254.ref037","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/B978-0-12-397925-4.00016-X","article-title":"Vascular endothelial growth factor A-stimulated signaling from endosomes in primary endothelial cells","volume":"535","author":"GW Fearnley","year":"2014","journal-title":"Methods Enzymol"},{"issue":"5","key":"pcbi.1013254.ref038","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1242\/bio.017434","article-title":"VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis","volume":"5","author":"GW Fearnley","year":"2016","journal-title":"Biol Open"},{"issue":"9","key":"pcbi.1013254.ref039","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1111\/j.1600-0854.2006.00462.x","article-title":"Intrinsic tyrosine kinase activity is required for vascular endothelial growth factor receptor 2 ubiquitination, sorting and degradation in endothelial cells","volume":"7","author":"LC Ewan","year":"2006","journal-title":"Traffic"},{"issue":"8","key":"pcbi.1013254.ref040","doi-asserted-by":"crossref","first-page":"2624","DOI":"10.1182\/blood-2005-12-007484","article-title":"VEGF regulates the mobilization of VEGFR2\/KDR from an intracellular endothelial storage compartment","volume":"108","author":"A Gampel","year":"2006","journal-title":"Blood"},{"issue":"2","key":"pcbi.1013254.ref041","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1011798","article-title":"Trafficking dynamics of VEGFR1, VEGFR2, and NRP1 in human endothelial cells","volume":"20","author":"S Sarabipour","year":"2024","journal-title":"PLoS Comput Biol"},{"issue":"3","key":"pcbi.1013254.ref042","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/ncb2679","article-title":"Spatial regulation of VEGF receptor endocytosis in angiogenesis","volume":"15","author":"M Nakayama","year":"2013","journal-title":"Nat Cell Biol"},{"issue":"6","key":"pcbi.1013254.ref043","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1002\/wsbm.92","article-title":"Systems biology of pro-angiogenic therapies targeting the VEGF system","volume":"2","author":"F Mac Gabhann","year":"2010","journal-title":"Wiley Interdiscip Rev Syst Biol Med"},{"issue":"3","key":"pcbi.1013254.ref044","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1111\/j.1582-4934.2009.00941.x","article-title":"A systems biology perspective on sVEGFR1: its biological function, pathogenic role and therapeutic use","volume":"14","author":"FTH Wu","year":"2010","journal-title":"J Cell Mol Med"},{"issue":"35","key":"pcbi.1013254.ref045","doi-asserted-by":"crossref","first-page":"26690","DOI":"10.1016\/S0021-9258(19)61431-6","article-title":"The interaction of neuropilin-1 with vascular endothelial growth factor and its receptor flt-1","volume":"275","author":"G Fuh","year":"2000","journal-title":"J Biol Chem"},{"issue":"2","key":"pcbi.1013254.ref046","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.bbamcr.2005.09.004","article-title":"Monte Carlo simulations of VEGF binding to cell surface receptors in vitro","volume":"1746","author":"F Mac Gabhann","year":"2005","journal-title":"Biochim Biophys Acta"},{"issue":"13","key":"pcbi.1013254.ref047","doi-asserted-by":"crossref","first-page":"4805","DOI":"10.1074\/jbc.M117.812172","article-title":"The Rab-effector protein RABEP2 regulates endosomal trafficking to mediate vascular endothelial growth factor receptor-2 (VEGFR2)-dependent signaling","volume":"293","author":"N Kofler","year":"2018","journal-title":"J Biol Chem"},{"key":"pcbi.1013254.ref048","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.bpc.2007.03.010","article-title":"Dimerization of VEGF receptors and implications for signal transduction: a computational study","volume":"128","author":"F Mac Gabhann","year":"2007","journal-title":"Biophys Chem"},{"issue":"21","key":"pcbi.1013254.ref049","doi-asserted-by":"crossref","first-page":"3366","DOI":"10.1093\/bioinformatics\/btw469","article-title":"BioNetGen 2.2: advances in rule-based modeling","volume":"32","author":"LA Harris","year":"2016","journal-title":"Bioinformatics"},{"issue":"12","key":"pcbi.1013254.ref050","doi-asserted-by":"crossref","first-page":"2993","DOI":"10.1158\/1078-0432.CCR-15-1839","article-title":"PlGF\/VEGFR-1 Signaling Promotes Macrophage Polarization and Accelerated Tumor Progression in Obesity","volume":"22","author":"J Incio","year":"2016","journal-title":"Clin Cancer Res"},{"issue":"2","key":"pcbi.1013254.ref051","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1161\/CIRCULATIONAHA.118.034165","article-title":"Antiangiogenic VEGF165b Regulates Macrophage Polarization via S100A8\/S100A9 in Peripheral Artery Disease","volume":"139","author":"VC Ganta","year":"2019","journal-title":"Circulation"},{"key":"pcbi.1013254.ref052","doi-asserted-by":"crossref","first-page":"15699","DOI":"10.1038\/ncomms15699","article-title":"Dynamic alterations in decoy VEGF receptor-1 stability regulate angiogenesis","volume":"8","author":"JM Boucher","year":"2017","journal-title":"Nat Commun"},{"issue":"6","key":"pcbi.1013254.ref053","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1004158","article-title":"Site-specific phosphorylation of VEGFR2 is mediated by receptor trafficking: insights from a computational model","volume":"11","author":"W Clegg","year":"2015","journal-title":"PLOS Comput Biol"},{"issue":"4","key":"pcbi.1013254.ref054","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1083\/jcb.200602080","article-title":"Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments","volume":"174","author":"MG Lampugnani","year":"2006","journal-title":"J Cell Biol"},{"issue":"45","key":"pcbi.1013254.ref055","doi-asserted-by":"crossref","first-page":"34009","DOI":"10.1074\/jbc.M603928200","article-title":"Phosphorylation of Tyr1214 within VEGFR-2 triggers the recruitment of Nck and activation of Fyn leading to SAPK2\/p38 activation and endothelial cell migration in response to VEGF","volume":"281","author":"L Lamalice","year":"2006","journal-title":"J Biol Chem"},{"issue":"12","key":"pcbi.1013254.ref056","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.1016\/j.cellsig.2013.08.015","article-title":"Computational model of VEGFR2 pathway to ERK activation and modulation through receptor trafficking","volume":"25","author":"WH Tan","year":"2013","journal-title":"Cell Signal"},{"issue":"5","key":"pcbi.1013254.ref057","article-title":"Endocytosis of receptor tyrosine kinases","volume":"5","author":"LK Goh","year":"2013","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"11","key":"pcbi.1013254.ref058","doi-asserted-by":"crossref","first-page":"7467","DOI":"10.1074\/jbc.M112.446401","article-title":"Essential role for endocytosis in the growth factor-stimulated activation of ERK1\/2 in endothelial cells","volume":"288","author":"M Gourlaouen","year":"2013","journal-title":"J Biol Chem"},{"issue":"6","key":"pcbi.1013254.ref059","article-title":"VEGF and soluble VEGF receptor-1 (sFlt-1) distributions in peripheral arterial disease: an in silico model","volume":"298","author":"FTH Wu","year":"2010","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"12","key":"pcbi.1013254.ref060","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1096\/fj.05-3889fje","article-title":"Regulatory role of dynamin-2 in VEGFR-2\/KDR-mediated endothelial signaling","volume":"19","author":"R Bhattacharya","year":"2005","journal-title":"FASEB J"},{"issue":"7","key":"pcbi.1013254.ref061","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1242\/dev.104539","article-title":"Dynamin 2 regulation of integrin endocytosis, but not VEGF signaling, is crucial for developmental angiogenesis","volume":"141","author":"MY Lee","year":"2014","journal-title":"Development"},{"issue":"2","key":"pcbi.1013254.ref062","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1021\/bp00014a007","article-title":"Mathematical model for the effects of epidermal growth factor receptor trafficking dynamics on fibroblast proliferation responses","volume":"8","author":"C Starbuck","year":"1992","journal-title":"Biotechnol Prog"},{"issue":"1","key":"pcbi.1013254.ref063","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0962-8924(02)00009-0","article-title":"Computational modeling of the EGF-receptor system: a paradigm for systems biology","volume":"13","author":"HS Wiley","year":"2003","journal-title":"Trends Cell Biol"},{"issue":"1","key":"pcbi.1013254.ref064","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1038\/s41467-022-28373-x","article-title":"Dual clathrin and integrin signaling systems regulate growth factor receptor activation","volume":"13","author":"MA Alfonzo-M\u00e9ndez","year":"2022","journal-title":"Nat Commun"},{"key":"pcbi.1013254.ref065","article-title":"Mechanistic computational modeling of sFLT1 secretion dynamics","author":"A Gill","year":"2025","journal-title":"bioRxiv"},{"issue":"4","key":"pcbi.1013254.ref066","first-page":"213","article-title":"An inside view: VEGF receptor trafficking and signaling","volume":"27","author":"M Simons","year":"2012","journal-title":"Physiology (Bethesda)"},{"issue":"6535","key":"pcbi.1013254.ref067","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/376066a0","article-title":"Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium","volume":"376","author":"GH Fong","year":"1995","journal-title":"Nature"},{"issue":"13","key":"pcbi.1013254.ref068","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1242\/dev.126.13.3015","article-title":"Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice","volume":"126","author":"GH Fong","year":"1999","journal-title":"Development"},{"issue":"12","key":"pcbi.1013254.ref069","doi-asserted-by":"crossref","first-page":"4527","DOI":"10.1182\/blood-2003-07-2315","article-title":"The VEGF receptor flt-1 (VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis","volume":"103","author":"JB Kearney","year":"2004","journal-title":"Blood"},{"issue":"5","key":"pcbi.1013254.ref070","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/S0002-9440(10)63711-X","article-title":"The vascular endothelial growth factor (VEGF) receptor Flt-1 (VEGFR-1) modulates Flk-1 (VEGFR-2) signaling during blood vessel formation","volume":"164","author":"DM Roberts","year":"2004","journal-title":"Am J Pathol"},{"issue":"2","key":"pcbi.1013254.ref071","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1161\/CIRCRESAHA.116.309516","article-title":"VEGF165b Modulates Endothelial VEGFR1-STAT3 Signaling Pathway and Angiogenesis in Human and Experimental Peripheral Arterial Disease","volume":"120","author":"VC Ganta","year":"2017","journal-title":"Circ Res"},{"issue":"12","key":"pcbi.1013254.ref072","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1242\/jcs.163774","article-title":"Autocrine VEGF maintains endothelial survival through regulation of metabolism and autophagy","volume":"128","author":"CK Domigan","year":"2015","journal-title":"J Cell Sci"},{"issue":"4","key":"pcbi.1013254.ref073","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.cell.2007.06.054","article-title":"Autocrine VEGF signaling is required for vascular homeostasis","volume":"130","author":"S Lee","year":"2007","journal-title":"Cell"},{"issue":"3","key":"pcbi.1013254.ref074","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/S0046-8177(87)80005-9","article-title":"Cell biology of endothelial cells","volume":"18","author":"EA Jaffe","year":"1987","journal-title":"Hum Pathol"},{"issue":"7","key":"pcbi.1013254.ref075","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/j.yexcr.2010.12.014","article-title":"Quantification and cell-to-cell variation of vascular endothelial growth factor receptors","volume":"317","author":"PI Imoukhuede","year":"2011","journal-title":"Exp Cell Res"},{"key":"pcbi.1013254.ref076","article-title":"A compartment model of VEGF distribution in humans in the presence of soluble VEGF receptor-1 acting as a ligand trap","volume":"4","author":"FTH Wu","year":"2009","journal-title":"PLoS ONE"},{"issue":"25","key":"pcbi.1013254.ref077","doi-asserted-by":"crossref","first-page":"17976","DOI":"10.1074\/jbc.M113.451831","article-title":"Proteolytic processing regulates placental growth factor activities","volume":"288","author":"DC Hoffmann","year":"2013","journal-title":"J Biol Chem"},{"key":"pcbi.1013254.ref078","doi-asserted-by":"crossref","first-page":"332","DOI":"10.4161\/cam.5.4.17287","article-title":"Overexpression of VEGF189 in breast cancer cells induces apoptosis via NRP1 under stress conditions","volume":"5","author":"N Vintonenko","year":"2011","journal-title":"Cell Adhes Migr"},{"issue":"3","key":"pcbi.1013254.ref079","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1005445","article-title":"A computational analysis of in vivo VEGFR activation by multiple co-expressed ligands","volume":"13","author":"LE Clegg","year":"2017","journal-title":"PLoS Comput Biol"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1013254","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1013254","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T17:46:42Z","timestamp":1753897602000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1013254"}},"subtitle":[],"editor":[{"given":"James","family":"Gallo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,7,16]]},"references-count":79,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1013254","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.09.29.615728","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,16]]}}}