{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T03:28:39Z","timestamp":1776310119272,"version":"3.50.1"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Syst Biol"],"published-print":{"date-parts":[[2007,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>In addition to initiating signaling events, the activation of cell surface receptors also triggers regulatory processes that restrict the duration of signaling. Acute attenuation of signaling can be accomplished either via ligand-induced internalization of receptors (<jats:italic>endocytic downregulation<\/jats:italic>) or via ligand-induced<jats:italic>receptor desensitization<\/jats:italic>. These phenomena have traditionally been viewed in the context of<jats:italic>adaptation<\/jats:italic>wherein the receptor system enters a refractory state in the presence of sustained ligand stimuli and thereby prevents the cell from over-responding to the ligand. Here we use the epidermal growth factor receptor (EGFR) and G-protein coupled receptors (GPCR) as model systems to respectively examine the effects of downregulation and desensitization on the ability of signaling receptors to decode time-varying ligand stimuli.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Using a mathematical model, we show that downregulation and desensitization mechanisms can lead to tight and efficient input-output coupling thereby ensuring synchronous processing of ligand inputs. Frequency response analysis indicates that upstream elements of the EGFR and GPCR networks behave like low-pass filters with the system being able to faithfully transduce inputs below a critical frequency. Receptor downregulation and desensitization increase the filter bandwidth thereby enabling the receptor systems to decode inputs in a wider frequency range. Further, system-theoretic analysis reveals that the receptor systems are analogous to classical mechanical over-damped systems. This analogy enables us to metaphorically describe downregulation and desensitization as phenomena that make the systems more resilient in responding to ligand perturbations thereby improving the stability of the system resting state.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings suggest that in addition to serving as mechanisms for adaptation, receptor downregulation and desensitization can play a critical role in temporal information processing. Furthermore, engineering metaphors such as the ones described here could prove to be invaluable in understanding the design principles of biological systems.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1752-0509-1-48","type":"journal-article","created":{"date-parts":[[2007,11,13]],"date-time":"2007-11-13T19:14:10Z","timestamp":1194981250000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Receptor downregulation and desensitization enhance the information processing ability of signalling receptors"],"prefix":"10.1186","volume":"1","author":[{"given":"Harish","family":"Shankaran","sequence":"first","affiliation":[]},{"given":"H Steven","family":"Wiley","sequence":"additional","affiliation":[]},{"given":"Haluk","family":"Resat","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2007,11,9]]},"reference":[{"key":"48_CR1","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1126\/science.1069981","volume":"295","author":"ME Csete","year":"2002","unstructured":"Csete ME, Doyle JC: Reverse engineering of biological complexity. Science. 2002, 295: 1664-1669. 10.1126\/science.1069981","journal-title":"Science"},{"key":"48_CR2","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/nature05127","volume":"443","author":"B Di Ventura","year":"2006","unstructured":"Di Ventura B, Lemerle C, Michalodimitrakis K, Serrano L: From in vivo to in silico biology and back. Nature. 2006, 443: 527-533. 10.1038\/nature05127","journal-title":"Nature"},{"key":"48_CR3","doi-asserted-by":"publisher","first-page":"2736","DOI":"10.1073\/pnas.0403510102","volume":"102","author":"H El-Samad","year":"2005","unstructured":"El-Samad H, Kurata H, Doyle JC, Gross CA, Khammash M: Surviving heat shock: control strategies for robustness and performance. Proc Natl Acad Sci USA. 2005, 102: 2736-2741. 10.1073\/pnas.0403510102","journal-title":"Proc Natl Acad Sci USA"},{"key":"48_CR4","doi-asserted-by":"publisher","first-page":"C47","DOI":"10.1038\/35011540","volume":"402","author":"LH Hartwell","year":"1999","unstructured":"Hartwell LH, Hopfield JJ, Leibler S, Murray AW: From molecular to modular cell biology. Nature. 1999, 402: C47-52. 10.1038\/35011540","journal-title":"Nature"},{"key":"48_CR5","doi-asserted-by":"publisher","first-page":"1662","DOI":"10.1126\/science.1069492","volume":"295","author":"H Kitano","year":"2002","unstructured":"Kitano H: Systems biology: a brief overview. Science. 2002, 295: 1662-1664. 10.1126\/science.1069492","journal-title":"Science"},{"key":"48_CR6","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/S0955-0674(03)00017-6","volume":"15","author":"JJ Tyson","year":"2003","unstructured":"Tyson JJ, Chen KC, Novak B: Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. Curr Opin Cell Biol. 2003, 15: 221-231. 10.1016\/S0955-0674(03)00017-6","journal-title":"Curr Opin Cell Biol"},{"key":"48_CR7","doi-asserted-by":"publisher","first-page":"4649","DOI":"10.1073\/pnas.97.9.4649","volume":"97","author":"TM Yi","year":"2000","unstructured":"Yi TM, Huang Y, Simon MI, Doyle J: Robust perfect adaptation in bacterial chemotaxis through integral feedback control. Proc Natl Acad Sci USA. 2000, 97: 4649-4653. 10.1073\/pnas.97.9.4649","journal-title":"Proc Natl Acad Sci USA"},{"key":"48_CR8","doi-asserted-by":"publisher","first-page":"1897","DOI":"10.1091\/mbc.12.6.1897","volume":"12","author":"P Burke","year":"2001","unstructured":"Burke P, Schooler K, Wiley HS: Regulation of epidermal growth factor receptor signaling by endocytosis and intracellular trafficking. Mol Biol Cell. 2001, 12: 1897-1910.","journal-title":"Mol Biol Cell"},{"key":"48_CR9","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1002\/bies.950150603","volume":"15","author":"A Sorkin","year":"1993","unstructured":"Sorkin A, Waters CM: Endocytosis of growth factor receptors. Bioessays. 1993, 15: 375-382. 10.1002\/bies.950150603","journal-title":"Bioessays"},{"key":"48_CR10","doi-asserted-by":"publisher","first-page":"2020","DOI":"10.1007\/s00018-003-3010-2","volume":"60","author":"D Teis","year":"2003","unstructured":"Teis D, Huber LA: The odd couple: signal transduction and endocytosis. Cell Mol Life Sci. 2003, 60: 2020-2033. 10.1007\/s00018-003-3010-2","journal-title":"Cell Mol Life Sci"},{"key":"48_CR11","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/S0014-4827(03)00002-8","volume":"284","author":"HS Wiley","year":"2003","unstructured":"Wiley HS: Trafficking of the ErbB receptors and its influence on signaling. Exp Cell Res. 2003, 284: 78-88. 10.1016\/S0014-4827(03)00002-8","journal-title":"Exp Cell Res"},{"key":"48_CR12","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1083\/jcb.115.6.1535","volume":"115","author":"JM Backer","year":"1991","unstructured":"Backer JM, Shoelson SE, Haring E, White MF: Insulin receptors internalize by a rapid, saturable pathway requiring receptor autophosphorylation and an intact juxtamembrane region. J Cell Biol. 1991, 115: 1535-1545. 10.1083\/jcb.115.6.1535","journal-title":"J Cell Biol"},{"key":"48_CR13","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1210\/me.2005-0170","volume":"20","author":"A Flores-Morales","year":"2006","unstructured":"Flores-Morales A, Greenhalgh CJ, Norstedt G, Rico-Bautista E: Negative regulation of growth hormone receptor signaling. Mol Endocrinol. 2006, 20: 241-253. 10.1210\/me.2005-0170","journal-title":"Mol Endocrinol"},{"key":"48_CR14","doi-asserted-by":"crossref","first-page":"11083","DOI":"10.1016\/S0021-9258(18)99131-3","volume":"266","author":"HS Wiley","year":"1991","unstructured":"Wiley HS, Herbst JJ, Walsh BJ, Lauffenburger DA, Rosenfeld MG, Gill GN: The role of tyrosine kinase activity in endocytosis, compartmentation, and down-regulation of the epidermal growth factor receptor. J Biol Chem. 1991, 266: 11083-11094.","journal-title":"J Biol Chem"},{"key":"48_CR15","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/S0014-4827(02)00098-8","volume":"284","author":"RN Jorissen","year":"2003","unstructured":"Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW: Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res. 2003, 284: 31-53. 10.1016\/S0014-4827(02)00098-8","journal-title":"Exp Cell Res"},{"key":"48_CR16","doi-asserted-by":"publisher","first-page":"962","DOI":"10.1126\/science.2305263","volume":"247","author":"A Wells","year":"1990","unstructured":"Wells A, Welsh JB, Lazar CS, Wiley HS, Gill GN, Rosenfeld MG: Ligand-induced transformation by a noninternalizing epidermal growth factor receptor. Science. 1990, 247: 962-964. 10.1126\/science.2305263","journal-title":"Science"},{"key":"48_CR17","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/S0962-8924(00)01795-5","volume":"10","author":"EB Leof","year":"2000","unstructured":"Leof EB: Growth factor receptor signalling: location, location, location. Trends Cell Biol. 2000, 10: 343-348. 10.1016\/S0962-8924(00)01795-5","journal-title":"Trends Cell Biol"},{"key":"48_CR18","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1006\/scdb.1997.0216","volume":"9","author":"SS Ferguson","year":"1998","unstructured":"Ferguson SS, Caron MG: G protein-coupled receptor adaptation mechanisms. Semin Cell Dev Biol. 1998, 9: 119-127. 10.1006\/scdb.1997.0216","journal-title":"Semin Cell Dev Biol"},{"key":"48_CR19","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1146\/annurev.neuro.27.070203.144206","volume":"27","author":"RR Gainetdinov","year":"2004","unstructured":"Gainetdinov RR, Premont RT, Bohn LM, Lefkowitz RJ, Caron MG: Desensitization of G protein-coupled receptors and neuronal functions. Annu Rev Neurosci. 2004, 27: 107-144. 10.1146\/annurev.neuro.27.070203.144206","journal-title":"Annu Rev Neurosci"},{"key":"48_CR20","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.1096\/fasebj.4.11.2165947","volume":"4","author":"WP Hausdorff","year":"1990","unstructured":"Hausdorff WP, Caron MG, Lefkowitz RJ: Turning off the signal: desensitization of beta-adrenergic receptor function. Faseb J. 1990, 4: 2881-2889.","journal-title":"Faseb J"},{"key":"48_CR21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0031-6997(24)01478-9","volume":"53","author":"SS Ferguson","year":"2001","unstructured":"Ferguson SS: Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev. 2001, 53: 1-24.","journal-title":"Pharmacol Rev"},{"key":"48_CR22","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1016\/S0006-3495(03)74516-0","volume":"85","author":"H Resat","year":"2003","unstructured":"Resat H, Ewald JA, Dixon DA, Wiley HS: An integrated model of epidermal growth factor receptor trafficking and signal transduction. Biophys J. 2003, 85: 730-743.","journal-title":"Biophys J"},{"key":"48_CR23","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1006\/jtbi.1999.0988","volume":"200","author":"TA Riccobene","year":"1999","unstructured":"Riccobene TA, Omann GM, Linderman JJ: Modeling activation and desensitization of G-protein coupled receptors provides insight into ligand efficacy. J Theor Biol. 1999, 200: 207-222. 10.1006\/jtbi.1999.0988","journal-title":"J Theor Biol"},{"key":"48_CR24","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/S0962-8924(02)00009-0","volume":"13","author":"HS Wiley","year":"2003","unstructured":"Wiley HS, Shvartsman SY, Lauffenburger DA: Computational modeling of the EGF-receptor system: a paradigm for systems biology. Trends Cell Biol. 2003, 13: 43-50. 10.1016\/S0962-8924(02)00009-0","journal-title":"Trends Cell Biol"},{"key":"48_CR25","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1016\/S1357-2725(99)00015-1","volume":"31","author":"A Wells","year":"1999","unstructured":"Wells A: EGF receptor. Int J Biochem Cell Biol. 1999, 31: 637-643. 10.1016\/S1357-2725(99)00015-1","journal-title":"Int J Biochem Cell Biol"},{"key":"48_CR26","doi-asserted-by":"publisher","first-page":"17949","DOI":"10.1074\/jbc.271.30.17949","volume":"271","author":"M Fannon","year":"1996","unstructured":"Fannon M, Nugent MA: Basic fibroblast growth factor binds its receptors, is internalized, and stimulates DNA synthesis in Balb\/c3T3 cells in the absence of heparan sulfate. J Biol Chem. 1996, 271: 17949-17956. 10.1074\/jbc.271.30.17949","journal-title":"J Biol Chem"},{"key":"48_CR27","doi-asserted-by":"crossref","first-page":"5623","DOI":"10.1016\/S0021-9258(18)91060-4","volume":"259","author":"DJ Knauer","year":"1984","unstructured":"Knauer DJ, Wiley HS, Cunningham DD: Relationship between epidermal growth factor receptor occupancy and mitogenic response. Quantitative analysis using a steady state model system. J Biol Chem. 1984, 259: 5623-5631.","journal-title":"J Biol Chem"},{"issue":"Pt 3","key":"48_CR28","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1042\/bj3230649","volume":"323","author":"HJ Harwood Jr","year":"1997","unstructured":"Harwood HJ, Pellarin LD: Kinetics of low-density lipoprotein receptor activity in Hep-G2 cells: derivation and validation of a Briggs-Haldane-based kinetic model for evaluating receptor-mediated endocytotic processes in which receptors recycle. Biochem J. 1997, 323 (Pt 3): 649-659.","journal-title":"Biochem J"},{"key":"48_CR29","doi-asserted-by":"publisher","first-page":"e101","DOI":"10.1371\/journal.pcbi.0030101","volume":"3","author":"H Shankaran","year":"2007","unstructured":"Shankaran H, Resat H, Wiley HS: Cell Surface Receptors for Signal Transduction and Ligand Transport: A Design Principles Study. PLoS Comput Biol. 2007, 3: e101- 10.1371\/journal.pcbi.0030101","journal-title":"PLoS Comput Biol"},{"key":"48_CR30","doi-asserted-by":"publisher","first-page":"3993","DOI":"10.1529\/biophysj.105.080580","volume":"90","author":"H Shankaran","year":"2006","unstructured":"Shankaran H, Wiley HS, Resat H: Modeling the effects of HER\/ErbB1-3 coexpression on receptor dimerization and biological response. Biophys J. 2006, 90: 3993-4009. 10.1529\/biophysj.105.080580","journal-title":"Biophys J"},{"key":"48_CR31","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1242\/jcs.114.12.2301","volume":"114","author":"AE DeWitt","year":"2001","unstructured":"DeWitt AE, Dong JY, Wiley HS, Lauffenburger DA: Quantitative analysis of the EGF receptor autocrine system reveals cryptic regulation of cell response by ligand capture. J Cell Sci. 2001, 114: 2301-2313.","journal-title":"J Cell Sci"},{"key":"48_CR32","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1002\/(SICI)1097-0290(19980305)57:5<571::AID-BIT9>3.0.CO;2-D","volume":"57","author":"GT Oehrtman","year":"1998","unstructured":"Oehrtman GT, Wiley HS, Lauffenburger DA: Escape of autocrine ligands into extracellular medium: experimental test of theoretical model predictions. Biotechnol Bioeng. 1998, 57: 571-582. 10.1002\/(SICI)1097-0290(19980305)57:5<571::AID-BIT9>3.0.CO;2-D","journal-title":"Biotechnol Bioeng"},{"key":"48_CR33","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1049\/ip-syb:20050057","volume":"153","author":"BS Hendriks","year":"2006","unstructured":"Hendriks BS, Cook J, Burke JM, Beusmans JM, Lauffenburger DA, de Graaf D: Computational modelling of ErbB family phosphorylation dynamics in response to transforming growth factor alpha and heregulin indicates spatial compartmentation of phosphatase activity. IEE Proc Syst Biol. 2006, 153: 22-33. 10.1049\/ip-syb:20050057","journal-title":"IEE Proc Syst Biol"},{"key":"48_CR34","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1038\/16483","volume":"397","author":"U Alon","year":"1999","unstructured":"Alon U, Surette MG, Barkai N, Leibler S: Robustness in bacterial chemotaxis. Nature. 1999, 397: 168-171. 10.1038\/16483","journal-title":"Nature"},{"issue":"Suppl 1","key":"48_CR35","doi-asserted-by":"publisher","first-page":"2538","DOI":"10.1073\/pnas.012582499","volume":"99","author":"JM Carlson","year":"2002","unstructured":"Carlson JM, Doyle J: Complexity and robustness. Proc Natl Acad Sci USA. 2002, 99 (Suppl 1): 2538-2545. 10.1073\/pnas.012582499","journal-title":"Proc Natl Acad Sci USA"},{"key":"48_CR36","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/j.cell.2004.09.008","volume":"118","author":"J Stelling","year":"2004","unstructured":"Stelling J, Sauer U, Szallasi Z, Doyle FJ, Doyle J: Robustness of cellular functions. Cell. 2004, 118: 675-685. 10.1016\/j.cell.2004.09.008","journal-title":"Cell"},{"key":"48_CR37","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1038\/35018085","volume":"406","author":"G von Dassow","year":"2000","unstructured":"von Dassow G, Meir E, Munro EM, Odell GM: The segment polarity network is a robust developmental module. Nature. 2000, 406: 188-192. 10.1038\/35018085","journal-title":"Nature"},{"key":"48_CR38","first-page":"319","volume":"51","author":"NJ Freedman","year":"1996","unstructured":"Freedman NJ, Lefkowitz RJ: Desensitization of G protein-coupled receptors. Recent Prog Horm Res. 1996, 51: 319-351. discussion 352-313.","journal-title":"Recent Prog Horm Res"},{"key":"48_CR39","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1002\/neu.10109","volume":"53","author":"MW Quick","year":"2002","unstructured":"Quick MW, Lester RA: Desensitization of neuronal nicotinic receptors. J Neurobiol. 2002, 53: 457-478. 10.1002\/neu.10109","journal-title":"J Neurobiol"},{"key":"48_CR40","first-page":"413","volume":"24","author":"PY Law","year":"1983","unstructured":"Law PY, Hom DS, Loh HH: Opiate receptor down-regulation and desensitization in neuroblastoma X glioma NG108-15 hybrid cells are two separate cellular adaptation processes. Mol Pharmacol. 1983, 24: 413-424.","journal-title":"Mol Pharmacol"},{"key":"48_CR41","doi-asserted-by":"publisher","first-page":"e154","DOI":"10.1371\/journal.pcbi.0020154","volume":"2","author":"BW Andrews","year":"2006","unstructured":"Andrews BW, Yi TM, Iglesias PA: Optimal noise filtering in the chemotactic response of Escherichia coli. PLoS Comput Biol. 2006, 2: e154- 10.1371\/journal.pcbi.0020154","journal-title":"PLoS Comput Biol"},{"key":"48_CR42","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1038\/nature01254","volume":"420","author":"H Kitano","year":"2002","unstructured":"Kitano H: Computational systems biology. Nature. 2002, 420: 206-210. 10.1038\/nature01254","journal-title":"Nature"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1752-0509-1-48.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T08:04:23Z","timestamp":1737533063000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/1752-0509-1-48"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,11,9]]},"references-count":42,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2007,12]]}},"alternative-id":["48"],"URL":"https:\/\/doi.org\/10.1186\/1752-0509-1-48","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,11,9]]},"assertion":[{"value":"15 May 2007","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 November 2007","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 November 2007","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"48"}}