{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T02:21:29Z","timestamp":1780366889301,"version":"3.54.1"},"reference-count":39,"publisher":"Elsevier BV","issue":"11","license":[{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T00:00:00Z","timestamp":1694044800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-HD085870"],"award-info":[{"award-number":["R01-HD085870"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-GM086537"],"award-info":[{"award-number":["R01-GM086537"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35-GM128813"],"award-info":[{"award-number":["R35-GM128813"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005883","name":"Hertz Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005883","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["jbc.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Biological Chemistry"],"published-print":{"date-parts":[[2023,11]]},"DOI":"10.1016\/j.jbc.2023.105234","type":"journal-article","created":{"date-parts":[[2023,9,9]],"date-time":"2023-09-09T17:50:54Z","timestamp":1694281854000},"page":"105234","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":4,"title":["Phase plane dynamics of ERK phosphorylation"],"prefix":"10.1016","volume":"299","author":[{"given":"Stanislav Y.","family":"Shvartsman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"McFann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0244-8947","authenticated-orcid":false,"given":"Martin","family":"W\u00fchr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris Y.","family":"Rubinstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.jbc.2023.105234_bib1","doi-asserted-by":"crossref","first-page":"R972","DOI":"10.1016\/j.cub.2013.09.033","article-title":"ERK as a model for systems biology of enzyme kinetics in cells","volume":"23","author":"Futran","year":"2013","journal-title":"Curr. Biol."},{"key":"10.1016\/j.jbc.2023.105234_bib2","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.phrs.2012.04.005","article-title":"ERK1\/2 MAP kinases: structure, function, and regulation","volume":"66","author":"Roskoski","year":"2012","journal-title":"Pharmacol. Res."},{"key":"10.1016\/j.jbc.2023.105234_bib3","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.bbrc.2011.11.145","article-title":"MEK1\/2 dual-specificity protein kinases: structure and regulation","volume":"417","author":"Roskoski","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"10.1016\/j.jbc.2023.105234_bib4","doi-asserted-by":"crossref","first-page":"19008","DOI":"10.1074\/jbc.272.30.19008","article-title":"Mechanistic studies of the dual phosphorylation of mitogen-activated protein kinase","volume":"272","author":"Ferrell","year":"1997","journal-title":"J.\u00a0Biol. Chem."},{"key":"10.1016\/j.jbc.2023.105234_bib5","doi-asserted-by":"crossref","first-page":"5929","DOI":"10.1021\/bi970535d","article-title":"The activating dual phosphorylation of MAPK by MEK is nonprocessive","volume":"36","author":"Burack","year":"1997","journal-title":"Biochemistry"},{"key":"10.1016\/j.jbc.2023.105234_bib6","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1016\/j.bpj.2014.09.024","article-title":"MAP kinase modules: the excursion model and the steps that count","volume":"107","author":"Piala","year":"2014","journal-title":"Biophys. J."},{"key":"10.1016\/j.jbc.2023.105234_bib7","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1091\/mbc.E20-10-0625","article-title":"Molecular mechanisms underlying cellular effects of human MEK1 mutations","volume":"32","author":"Marmion","year":"2021","journal-title":"Mol. Biol. Cell"},{"key":"10.1016\/j.jbc.2023.105234_bib8","doi-asserted-by":"crossref","first-page":"18814","DOI":"10.1074\/jbc.C117.806067","article-title":"How activating mutations affect MEK1 regulation and function","volume":"292","author":"Jindal","year":"2017","journal-title":"J.\u00a0Biol. Chem."},{"key":"10.1016\/j.jbc.2023.105234_bib9","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1093\/bfgp\/els022","article-title":"MEK genomics in development and disease","volume":"11","author":"Bromberg-White","year":"2012","journal-title":"Brief. Funct. Genomics"},{"key":"10.1016\/j.jbc.2023.105234_bib10","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.ajhg.2020.06.018","article-title":"Enhanced MAPK1 function causes a neurodevelopmental disorder within the RASopathy clinical spectrum","volume":"107","author":"Motta","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"10.1016\/j.jbc.2023.105234_bib11","doi-asserted-by":"crossref","first-page":"15514","DOI":"10.1073\/pnas.1905015116","article-title":"Functional divergence caused by mutations in an energetic hotspot in ERK2","volume":"116","author":"Taylor","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.jbc.2023.105234_bib12","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1073\/pnas.1615651114","article-title":"In\u00a0vivo severity ranking of Ras pathway mutations associated with developmental disorders","volume":"114","author":"Jindal","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.jbc.2023.105234_bib13","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1242\/dmm.020339","article-title":"RASopathies: unraveling mechanisms with animal models","volume":"8","author":"Jindal","year":"2015","journal-title":"Dis. Model. Mech."},{"key":"10.1016\/j.jbc.2023.105234_bib14","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/ng.3780","article-title":"Divergent effects of intrinsically active MEK variants on developmental Ras signaling","volume":"49","author":"Goyal","year":"2017","journal-title":"Nat. Genet."},{"key":"10.1016\/j.jbc.2023.105234_bib15","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.cub.2023.01.008","article-title":"Stochastic phenotypes in RAS-dependent developmental diseases","volume":"33","author":"Marmion","year":"2023","journal-title":"Curr. Biol."},{"key":"10.1016\/j.jbc.2023.105234_bib16","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s11538-022-01088-2","article-title":"Algebra, geometry and topology of ERK kinetics","volume":"84","author":"Marsh","year":"2022","journal-title":"Bull. Math. Biol."},{"key":"10.1016\/j.jbc.2023.105234_bib17","doi-asserted-by":"crossref","DOI":"10.1103\/PhysRevLett.104.060201","article-title":"Why are nonlinear fits to data so challenging?","volume":"104","author":"Transtrum","year":"2010","journal-title":"Phys. Rev. Lett."},{"key":"10.1016\/j.jbc.2023.105234_bib18","doi-asserted-by":"crossref","first-page":"15529","DOI":"10.1021\/bi961854s","article-title":"Interdependent domains controlling the enzymatic activity of mitogen-activated protein kinase kinase 1","volume":"35","author":"Mansour","year":"1996","journal-title":"Biochemistry"},{"key":"10.1016\/j.jbc.2023.105234_bib19","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.cub.2019.12.052","article-title":"Inference of multisite phosphorylation rate constants and their modulation by pathogenic mutations","volume":"30","author":"Yeung","year":"2020","journal-title":"Curr. Biol."},{"key":"10.1016\/j.jbc.2023.105234_bib20","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1007\/s00285-021-01574-6","article-title":"Dynamics of ERK regulation in the processive limit","volume":"82","author":"Conradi","year":"2021","journal-title":"J.\u00a0Math. Biol."},{"key":"10.1016\/j.jbc.2023.105234_bib21","series-title":"Introduction to the Foundations of Applied Mathematics","author":"Holmes","year":"2009"},{"key":"10.1016\/j.jbc.2023.105234_bib22","doi-asserted-by":"crossref","first-page":"12675","DOI":"10.1073\/pnas.1104030108","article-title":"Processive phosphorylation of ERK MAP kinase in mammalian cells","volume":"108","author":"Aoki","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.jbc.2023.105234_bib23","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.1073\/pnas.0906885107","article-title":"Spatio-temporal correlations can drastically change the response of a MAPK pathway","volume":"107","author":"Takahashi","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.jbc.2023.105234_bib24","doi-asserted-by":"crossref","first-page":"19784","DOI":"10.1073\/pnas.1319943110","article-title":"Diffusion modifies the connectivity of kinetic schemes for multisite binding and catalysis","volume":"110","author":"Gopich","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.jbc.2023.105234_bib25","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/ng.1026","article-title":"Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma","volume":"44","author":"Nikolaev","year":"2011","journal-title":"Nat. Genet."},{"key":"10.1016\/j.jbc.2023.105234_bib26","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1093\/hmg\/ddm319","article-title":"Germline mutations of MEK in cardio-facio-cutaneous syndrome are sensitive to MEK and RAF inhibition: implications for therapeutic options","volume":"17","author":"Senawong","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"10.1016\/j.jbc.2023.105234_bib27","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-018-30202-5","article-title":"Intrinsically active MEK variants are differentially regulated by proteinases and phosphatases","volume":"8","author":"Ordan","year":"2018","journal-title":"Sci. Rep."},{"key":"10.1016\/j.jbc.2023.105234_bib28","doi-asserted-by":"crossref","first-page":"R222","DOI":"10.1016\/j.cub.2020.01.039","article-title":"Cancer mutations: molecular MEKanisms","volume":"30","author":"Bardwell","year":"2020","journal-title":"Curr. Biol."},{"key":"10.1016\/j.jbc.2023.105234_bib29","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1146\/annurev-genom-091212-153523","article-title":"The RASopathies","volume":"14","author":"Rauen","year":"2013","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"10.1016\/j.jbc.2023.105234_bib30","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1006\/jtbi.1996.0167","article-title":"Nonlinear enzyme kinetics can lead to high metabolic flux control coefficients: implications for the evolution of dominance","volume":"182","author":"Grossniklaus","year":"1996","journal-title":"J.\u00a0Theor. Biol."},{"key":"10.1016\/j.jbc.2023.105234_bib31","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1534\/genetics.104.028696","article-title":"Evolution of dominance in metabolic pathways","volume":"168","author":"Bagheri","year":"2004","journal-title":"Genetics"},{"key":"10.1016\/j.jbc.2023.105234_bib32","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1006\/jtbi.1996.0159","article-title":"Dominance--one hundred and fifteen years after Mendel\u2019s paper","volume":"182","author":"Porteous","year":"1996","journal-title":"J.\u00a0Theor. Biol."},{"key":"10.1016\/j.jbc.2023.105234_bib33","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1093\/genetics\/97.3-4.639","article-title":"The molecular basis of dominance","volume":"97","author":"Kacser","year":"1981","journal-title":"Genetics"},{"key":"10.1016\/j.jbc.2023.105234_bib34","doi-asserted-by":"crossref","first-page":"35526","DOI":"10.1074\/jbc.274.50.35526","article-title":"Mechanism of mitogen-activated protein kinase phosphatase-3 activation by ERK2","volume":"274","author":"Zhou","year":"1999","journal-title":"J.\u00a0Biol. Chem."},{"key":"10.1016\/j.jbc.2023.105234_bib35","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1091\/mbc.E16-03-0137","article-title":"Long-term dynamics of multisite phosphorylation","volume":"27","author":"Rubinstein","year":"2016","journal-title":"Mol. Biol. Cell"},{"key":"10.1016\/j.jbc.2023.105234_bib36","doi-asserted-by":"crossref","DOI":"10.1093\/pnasnexus\/pgac154","article-title":"On the parameter combinations that matter and on those that do not: data-driven studies of parameter (non)identifiability","volume":"1","author":"Evangelou","year":"2022","journal-title":"PNAS Nexus"},{"key":"10.1016\/j.jbc.2023.105234_bib37","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.molonc.2014.01.003","article-title":"Differential activity of MEK and ERK inhibitors in BRAF inhibitor resistant melanoma","volume":"8","author":"Carlino","year":"2014","journal-title":"Mol. Oncol."},{"key":"10.1016\/j.jbc.2023.105234_bib38","doi-asserted-by":"crossref","first-page":"8697","DOI":"10.1073\/pnas.0602767103","article-title":"Understanding bistability in complex enzyme-driven reaction networks","volume":"103","author":"Craciun","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.jbc.2023.105234_bib39","doi-asserted-by":"crossref","DOI":"10.1098\/rsfs.2022.0013","article-title":"The linear framework: using graph theory to reveal the algebra and thermodynamics of biomolecular systems","volume":"12","author":"Nam","year":"2022","journal-title":"Interface Focus"}],"container-title":["Journal of Biological Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0021925823022627?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0021925823022627?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T20:55:12Z","timestamp":1777409712000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0021925823022627"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11]]},"references-count":39,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2023,11]]}},"alternative-id":["S0021925823022627"],"URL":"https:\/\/doi.org\/10.1016\/j.jbc.2023.105234","relation":{},"ISSN":["0021-9258"],"issn-type":[{"value":"0021-9258","type":"print"}],"subject":[],"published":{"date-parts":[[2023,11]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Phase plane dynamics of ERK phosphorylation","name":"articletitle","label":"Article Title"},{"value":"Journal of Biological Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.jbc.2023.105234","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2023 The Authors. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology.","name":"copyright","label":"Copyright"}],"article-number":"105234"}}