{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:13:46Z","timestamp":1772172826890,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009125","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T00:00:00Z","timestamp":1626134400000}}],"reference-count":58,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T00:00:00Z","timestamp":1625011200000},"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":["P30 CA047904"],"award-info":[{"award-number":["P30 CA047904"]}],"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":["U01CA204826"],"award-info":[{"award-number":["U01CA204826"]}],"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":["1UL1TR001857"],"award-info":[{"award-number":["1UL1TR001857"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Aberrant signaling through insulin (Ins) and insulin-like growth factor I (IGF1) receptors contribute to the risk and advancement of many cancer types by activating cell survival cascades. Similarities between these pathways have thus far prevented the development of pharmacological interventions that specifically target either Ins or IGF1 signaling. To identify differences in early Ins and IGF1 signaling mechanisms, we developed a dual receptor (IGF1R &amp; InsR) computational response model. The model suggested that ribosomal protein S6 kinase (RPS6K) plays a critical role in regulating MAPK and Akt activation levels in response to Ins and IGF1 stimulation. As predicted, perturbing RPS6K kinase activity led to an increased Akt activation with Ins stimulation compared to IGF1 stimulation. Being able to discern differential downstream signaling, we can explore improved anti-IGF1R cancer therapies by eliminating the emergence of compensation mechanisms without disrupting InsR signaling.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009125","type":"journal-article","created":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T13:48:47Z","timestamp":1625060927000},"page":"e1009125","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Inhibition of RPS6K reveals context-dependent Akt activity in luminal breast cancer cells"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3663-3646","authenticated-orcid":true,"given":"Cemal","family":"Erdem","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9917-514X","authenticated-orcid":true,"given":"Adrian V.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6947-1343","authenticated-orcid":true,"given":"D. Lansing","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9802-3961","authenticated-orcid":true,"given":"Timothy R.","family":"Lezon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,6,30]]},"reference":[{"key":"pcbi.1009125.ref001","doi-asserted-by":"crossref","first-page":"5178","DOI":"10.1210\/endo.140.11.7151","article-title":"Insulin-like growth factor I is essential for postnatal growth in response to growth hormone","volume":"140","author":"JL Liu","year":"1999","journal-title":"Endocrinology"},{"key":"pcbi.1009125.ref002","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.7150\/ijbs.7.1003","article-title":"The Link between the Metabolic Syndrome and Cancer","volume":"7","author":"S Braun","year":"2011","journal-title":"Int J Biol Sci"},{"key":"pcbi.1009125.ref003","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.cytogfr.2006.02.002","article-title":"Regulation of apoptosis by insulin-like growth factor (IGF)-I","volume":"17","author":"R Kooijman","year":"2006","journal-title":"Cytokine Growth Factor Rev"},{"key":"pcbi.1009125.ref004","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/414799a","article-title":"Insulin signalling and the regulation of glucose and lipid metabolism","volume":"414","author":"AR Saltiel","year":"2001","journal-title":"Nature"},{"key":"pcbi.1009125.ref005","doi-asserted-by":"crossref","first-page":"3273","DOI":"10.2741\/2925","article-title":"The type I insulin-like growth factor receptor pathway: a key player in cancer therapeutic resistance","volume":"13","author":"AJ Casa","year":"2008","journal-title":"Front Biosci"},{"key":"pcbi.1009125.ref006","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1615\/CritRevOncog.v17.i2.30","article-title":"Targeting the insulin-like growth factor receptor: developing biomarkers from gene expression profiling","volume":"17","author":"DN Boone","year":"2012","journal-title":"Crit Rev Oncog"},{"key":"pcbi.1009125.ref007","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/nrc3967","article-title":"Adiposity and cancer risk: new mechanistic insights from epidemiology","volume":"15","author":"AG Renehan","year":"2015","journal-title":"Nat Rev Cancer"},{"key":"pcbi.1009125.ref008","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1038\/nrc3174","article-title":"Molecular mechanisms of cancer development in obesity","volume":"11","author":"MJ Khandekar","year":"2011","journal-title":"Nat Rev Cancer"},{"key":"pcbi.1009125.ref009","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/nrc1387","article-title":"Insulin-like growth factors and neoplasia","volume":"4","author":"MN Pollak","year":"2004","journal-title":"Nat Rev Cancer"},{"key":"pcbi.1009125.ref010","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1038\/nrc2536","article-title":"Insulin and insulin-like growth factor signalling in neoplasia","volume":"8","author":"M Pollak","year":"2008","journal-title":"Nat Rev Cancer"},{"key":"pcbi.1009125.ref011","first-page":"303","article-title":"Insulin-Like Growth Factor Signaling in Normal Mammary Gland Development and Breast Cancer Progression","author":"A Casa","year":"2008","journal-title":"Breast Cancer Progn Treat Prev"},{"key":"pcbi.1009125.ref012","doi-asserted-by":"crossref","first-page":"4985","DOI":"10.1200\/JCO.2009.27.5040","article-title":"Small is beautiful: insulin-like growth factors and their role in growth, development, and cancer","volume":"28","author":"RG Maki","year":"2010","journal-title":"J Clin Oncol"},{"key":"pcbi.1009125.ref013","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.tem.2010.06.007","article-title":"The proliferating role of insulin and insulin-like growth factors in cancer","volume":"21","author":"EJ Gallagher","year":"2010","journal-title":"Trends Endocrinol Metab"},{"key":"pcbi.1009125.ref014","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1530\/JME-11-0022","article-title":"Signalling by insulin and IGF receptors: supporting acts and new players","volume":"47","author":"K Siddle","year":"2011","journal-title":"J Mol Endocrinol"},{"key":"pcbi.1009125.ref015","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrendo.2010.171","article-title":"Growth hormone, the insulin-like growth factor axis, insulin and cancer risk","volume":"7","author":"PE Clayton","year":"2011","journal-title":"Nat Rev Endocrinol"},{"key":"pcbi.1009125.ref016","first-page":"4","article-title":"Targeting the insulin-like growth factor-1 receptor in human cancer","author":"A Arcaro","year":"2013","journal-title":"Front Pharmacol"},{"key":"pcbi.1009125.ref017","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1007\/s11523-017-0514-5","article-title":"Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future Combination Studies","volume":"12","author":"A Simpson","year":"2017","journal-title":"Target Oncol"},{"key":"pcbi.1009125.ref018","doi-asserted-by":"crossref","first-page":"2447","DOI":"10.1158\/1535-7163.MCT-10-0719","article-title":"Targeting insulin-like growth factor signaling: rational combination strategies","volume":"9","author":"D Olmos","year":"2010","journal-title":"Mol Cancer Ther"},{"key":"pcbi.1009125.ref019","doi-asserted-by":"crossref","first-page":"15019","DOI":"10.1038\/nrdp.2015.19","article-title":"Type 2 diabetes mellitus","volume":"1","author":"RA DeFronzo","year":"2015","journal-title":"Nat Rev Primer"},{"key":"pcbi.1009125.ref020","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1677\/erc.0.0080197","article-title":"The IGF system and breast cancer","volume":"8","author":"D Sachdev","year":"2001","journal-title":"Endocr Relat Cancer"},{"key":"pcbi.1009125.ref021","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/nature11781","article-title":"How insulin engages its primary binding site on the insulin receptor","volume":"493","author":"JG Menting","year":"2013","journal-title":"Nature"},{"key":"pcbi.1009125.ref022","first-page":"3","article-title":"How IGF-1 Activates its Receptor","author":"JM Kavran","year":"2014","journal-title":"Elife"},{"key":"pcbi.1009125.ref023","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.str.2011.03.014","article-title":"Fine Details of IGF-1R Activation, Inhibition, and Asymmetry Determined by Associated Hydrogen\/Deuterium-Exchange and Peptide Mass Mapping","volume":"19","author":"D Houde","year":"2011","journal-title":"Structure"},{"key":"pcbi.1009125.ref024","first-page":"5","article-title":"Harmonic oscillator model of the insulin and IGF1 receptors\u2019 allosteric binding and activation","author":"VV Kiselyov","year":"2009","journal-title":"Mol Syst Biol"},{"key":"pcbi.1009125.ref025","doi-asserted-by":"crossref","first-page":"3045","DOI":"10.1074\/mcp.M115.057729","article-title":"Proteomic Screening and Lasso Regression Reveal Differential Signaling in Insulin and Insulin-like Growth Factor I (IGF1) Pathways","volume":"15","author":"C Erdem","year":"2016","journal-title":"Mol Cell Proteomics"},{"issue":"20","key":"pcbi.1009125.ref026","doi-asserted-by":"crossref","first-page":"5165","DOI":"10.1158\/1078-0432.CCR-18-0279","article-title":"Loss of E-cadherin Enhances IGF1\u2013IGF1R Pathway Activation and Sensitizes Breast Cancers to Anti-IGF1R\/InsR Inhibitors","volume":"24","author":"AM Nagle","year":"2018","journal-title":"Clin Cancer Res"},{"key":"pcbi.1009125.ref027","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.biotechadv.2012.11.001","article-title":"Computational model of EGFR and IGF1R pathways in lung cancer: A Systems Biology approach for Translational Oncology (vol 30, pg 142, 2012)","volume":"31","author":"F Bianconi","year":"2013","journal-title":"Biotechnol Adv"},{"key":"pcbi.1009125.ref028","first-page":"9","article-title":"Integrating network reconstruction with mechanistic modeling to predict cancer therapies","author":"M Halasz","year":"2016","journal-title":"Sci Signal"},{"key":"pcbi.1009125.ref029","doi-asserted-by":"crossref","first-page":"E1084","DOI":"10.1152\/ajpendo.00571.2001","article-title":"A mathematical model of metabolic insulin signaling pathways","volume":"283","author":"AR Sedaghat","year":"2002","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"pcbi.1009125.ref030","first-page":"5","article-title":"Systems-level interactions between insulin-EGF networks amplify mitogenic signaling","author":"N Borisov","year":"2009","journal-title":"Mol Syst Biol"},{"key":"pcbi.1009125.ref031","first-page":"14","article-title":"A mechanistic pan-cancer pathway model informed by multi-omics data interprets stochastic cell fate responses to drugs and mitogens","author":"M Bouhaddou","year":"2018","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1009125.ref032","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"},{"key":"pcbi.1009125.ref033","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1073\/pnas.0711713105","article-title":"Dissection of the insulin signaling pathway via quantitative phosphoproteomics","volume":"105","author":"M Kruger","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1009125.ref034","doi-asserted-by":"crossref","first-page":"14892","DOI":"10.1038\/ncomms14892","article-title":"Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression","volume":"8","author":"W Cai","year":"2017","journal-title":"Nat Commun"},{"issue":"1","key":"pcbi.1009125.ref035","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/0959-437X(94)90090-6","article-title":"The IRS-1 signaling system","volume":"4","author":"MF White","year":"1994","journal-title":"Curr Opin Genet Dev"},{"issue":"6","key":"pcbi.1009125.ref036","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1093\/hmg\/10.6.605","article-title":"PTEN inhibits insulin-stimulated MEK\/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1\/Grb-2\/Sos complex formation in a breast cancer model","volume":"10","author":"L-P Weng","year":"2002","journal-title":"Hum Mol Genet"},{"issue":"15","key":"pcbi.1009125.ref037","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1101\/gad.1110003","article-title":"Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling","volume":"17","author":"K Inoki","year":"2003","journal-title":"Genes Dev"},{"issue":"8","key":"pcbi.1009125.ref038","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.cub.2005.02.053","article-title":"Rheb Binds and Regulates the mTOR Kinase","volume":"15","author":"X Long","year":"2005","journal-title":"Curr Biol"},{"issue":"6","key":"pcbi.1009125.ref039","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.tibs.2011.03.006","article-title":"The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation","volume":"36","author":"MC Mendoza","year":"2011","journal-title":"Trends Biochem Sci"},{"issue":"1","key":"pcbi.1009125.ref040","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/1752-0509-6-82","article-title":"Different designs of kinase-phosphatase interactions and phosphatase sequestration shapes the robustness and signal flow in the MAPK cascade","volume":"6","author":"U Sarma","year":"2012","journal-title":"BMC Syst Biol"},{"key":"pcbi.1009125.ref041","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1038\/nbt0402-370","article-title":"Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors","volume":"20","author":"B Schoeberl","year":"2002","journal-title":"Nat Biotechnol"},{"issue":"3","key":"pcbi.1009125.ref042","doi-asserted-by":"crossref","first-page":"035006","DOI":"10.1088\/1478-3975\/10\/3\/035006","article-title":"MEK1 and MEK2 differentially control the duration and amplitude of the ERK cascade response","volume":"10","author":"P Kocieniewski","year":"2013","journal-title":"Phys Biol"},{"issue":"1","key":"pcbi.1009125.ref043","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/1752-0509-6-107","article-title":"Specification, annotation, visualization and simulation of a large rule-based model for ERBB receptor signaling","volume":"6","author":"MS Creamer","year":"2012","journal-title":"BMC Syst Biol"},{"key":"pcbi.1009125.ref044","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1093\/bioinformatics\/btr197","article-title":"RuleBender: a visual interface for rule-based modeling","volume":"27","author":"W Xu","year":"2011","journal-title":"Bioinformatics"},{"key":"pcbi.1009125.ref045","first-page":"9","article-title":"Programming biological models in Python using PySB","author":"CF Lopez","year":"2013","journal-title":"Mol Syst Biol"},{"key":"pcbi.1009125.ref046","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.tcs.2004.03.065","article-title":"Formal molecular biology","volume":"325","author":"V Danos","year":"2004","journal-title":"Theor Comput Sci"},{"key":"pcbi.1009125.ref047","doi-asserted-by":"crossref","unstructured":"Gupta S, Hainsworth L, Hogg J, Lee R, Faeder J. Evaluation of Parallel Tempering to Accelerate Bayesian Parameter Estimation in Systems Biology. In: 2018 26th Euromicro International Conference on Parallel, Distributed and Network-based Processing (PDP). 2018. p. 690\u20137.","DOI":"10.1109\/PDP2018.2018.00114"},{"issue":"2","key":"pcbi.1009125.ref048","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.cels.2018.06.002","article-title":"Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling","volume":"7","author":"OS Rukhlenko","year":"2018","journal-title":"Cell Syst"},{"key":"pcbi.1009125.ref049","author":"S Klaeger","journal-title":"The target landscape of clinical kinase drugs"},{"key":"pcbi.1009125.ref050","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/nrm1837","article-title":"Critical nodes in signalling pathways: insights into insulin action","volume":"7","author":"CM Taniguchi","year":"2006","journal-title":"Nat Rev Mol Cell Biol"},{"key":"pcbi.1009125.ref051","doi-asserted-by":"crossref","first-page":"rs6","DOI":"10.1126\/scisignal.aaf0891","article-title":"Conservation of protein abundance patterns reveals the regulatory architecture of the EGFR-MAPK pathway","volume":"9","author":"T Shi","year":"2016","journal-title":"Sci Signal"},{"key":"pcbi.1009125.ref052","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1177\/1087057116635818","article-title":"A Perspective on Implementing a Quantitative Systems Pharmacology Platform for Drug Discovery and the Advancement of Personalized Medicine","volume":"21","author":"AM Stern","year":"2016","journal-title":"J Biomol Screen"},{"key":"pcbi.1009125.ref053","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1002\/cpt.528","article-title":"Quantitative Systems Pharmacology: A Case for Disease Models","volume":"101","author":"CJ Musante","year":"2017","journal-title":"Clin Pharmacol Ther"},{"key":"pcbi.1009125.ref054","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1146\/annurev-pharmtox-010611-134520","article-title":"Systems pharmacology: network analysis to identify multiscale mechanisms of drug action","volume":"52","author":"S Zhao","year":"2012","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"pcbi.1009125.ref055","doi-asserted-by":"crossref","first-page":"2512","DOI":"10.1158\/1535-7163.MCT-06-0334","article-title":"Reverse phase protein array: validation of a novel proteomic technology and utility for analysis of primary leukemia specimens and hematopoietic stem cells","volume":"5","author":"R Tibes","year":"2006","journal-title":"Mol Cancer Ther"},{"key":"pcbi.1009125.ref056","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.ymeth.2017.06.017","article-title":"Protein network construction using reverse phase protein array data","volume":"124","author":"RS Varghese","year":"2017","journal-title":"Methods"},{"key":"pcbi.1009125.ref057","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1515\/9783110288537.19","volume-title":"Mathematics and Life Sciences","author":"D Swigon","year":"2012"},{"issue":"2","key":"pcbi.1009125.ref058","doi-asserted-by":"crossref","first-page":"21904","DOI":"10.1103\/PhysRevE.68.021904","article-title":"Statistical mechanical approaches to models with many poorly known parameters","volume":"68","author":"KS Brown","year":"2003","journal-title":"Phys Rev E"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1009125","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T00:00:00Z","timestamp":1626134400000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009125","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,1]],"date-time":"2023-01-01T23:50:03Z","timestamp":1672617003000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009125"}},"subtitle":[],"editor":[{"given":"Benjamin","family":"Hall","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,6,30]]},"references-count":58,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6,30]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1009125","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.10.22.349647","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,30]]}}}