title: Affinity regulates spatial range of EGF receptor autocrine ligand binding.
abstract: Proper spatial localization of EGFR signaling activated by autocrine ligands represents a critical factor in embryonic development as well as tissue organization and function, and ligand/receptor binding affinity is among the molecular and cellular properties suggested to play a role in governing this localization. We employ a computational model to predict how receptor-binding affinity affects local capture of autocrine ligand vis-a-vis escape to distal regions, and provide experimental test by constructing cell lines expressing EGFR along with either wild-type EGF or a low-affinity mutant, EGF(L47M). The model predicts local capture of a lower affinity autocrine ligand to be less efficient when the ligand production rate is small relative to receptor appearance rate. Our experimental data confirm this prediction, demonstrating that cells can use ligand/receptor binding affinity to regulate ligand spatial distribution when autocrine ligand production is limiting for receptor signaling.
authors.affiliation: Department of Chemical Engineering, Center for Cancer Research, Massachusetts Institute of Technology, Cambridge 02139, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: DeWitt
authors.forename: Tomoko
authors.initials: T
authors.lastname: Iida
authors.forename: Ho-Yan
authors.initials: HY
authors.lastname: Lam
authors.forename: Virginia
authors.initials: V
authors.lastname: Hill
authors.forename: H Steven
authors.initials: HS
authors.lastname: Wiley
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D008024:Ligands; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors