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An integrated mechanistic model of TGF-β-triggered ERK activation and its crosstalk with SMAD dynamics shows ERK-mediated linker phosphorylation changes SMAD transcription timing and strength, mediated by receptor turnover via lipid rafts.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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main focus of the computational model in this study?","Question",{"text":63,"@type":64},"The study builds an integrated mechanistic model of the TGF-β-triggered ERK activation pathway and analyzes its crosstalk with the SMAD pathway to explain how SMAD dynamics are reshaped by ERK signaling.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How does ERK signaling affect SMAD-dependent transcription after TGF-β stimulation?",{"text":68,"@type":64},"The model indicates that SMAD-mediated transcription can be altered and delayed due to expedited phosphorylation of the SMAD linker by TGF-β-activated ERK.",{"name":70,"@type":61,"acceptedAnswer":71},"What signaling differences does the model predict between normal and cancerous cells?",{"text":72,"@type":64},"Normal cells are predicted to show enhanced, sustained SMAD signaling with transient ERK activation, while cancerous cells show elevated, prolonged ERK signaling with attenuated SMAD 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[https://doi.org/10.1101/2024.11.07.622480](https://doi.org/10.1101/2024.11.07.622480); this version posted November 9, 2024. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made  \navailable under aCC-BY-NC-ND 4.0 International license.  \nComputational Modeling and Analysis of the TGF-β-induced ERK and SMAD Pathways  \nSeung-Wook Chung 1, Carlton R. Cooper 2, Mary C. Farach-Carson 3, and Babatunde A. Ogunnaike 1, *  \n1 Department of Chemical & Biomolecular Engineering; University of Delaware, Newark DE,  \nU. S.A.  \n2 Departments of Biological Sciences & Black American Studies, University of Delaware, Newark DE, U. S.A.  \n3 Departments of BioSciences and Bioengineering, Rice University, Houston, TX, U. S.A.  \nAuthors’Email Addresses:  \nChung, [S.W. ](S.W.  seung.chung@boehringer-ingelheim.com)[ seung.chung@boehringer-ingelheim.com](S.W.  seung.chung@boehringer-ingelheim.com)  \nCooper, [C.R. ](C.R.  crcooper@udel.edu)[ crcooper@udel.edu](C.R.  crcooper@udel.edu)  \nFarach-Carson, [M.C. ](M.C.  farachca@rice.edu)[ farachca@rice.edu](M.C.  farachca@rice.edu)  \nOgunnaike, [B.A. ](B.A.  ogunnaike@udel.edu)[ ogunnaike@udel.edu](B.A.  ogunnaike@udel.edu)  \nbioRxiv preprint doi: [https://doi.org/10.1101/2024.11.07.622480](https://doi.org/10.1101/2024.11.07.622480); this version posted November 9, 2024. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made  \navailable under aCC-BY-NC-ND 4.0 International license.  \nAbstract  \nTGF-β, an important cytokine that plays a key role in many diseases regulates a wide array of cellular and physiologic processes via several TGF-β-driven signaling cascades, including the SMAD and nonSMAD-driven pathways. However, the detailed mechanisms by which TGF-β induces such diverse responses remain poorly understood. In particular, compared to the SMAD-dependent pathway, SMAD-independent pathways such as the ERK/MAPK pathway, which is critical in cancer progression, are less characterized. Here, we develop an integrated mechanistic model ofthe TGF-β -triggered ERK activation pathway and its crosstalk with the SMAD pathway, an analysis of which demonstrates how SMAD dynamics can be significantly modulated and regulated by the ERK pathway. In particular, SMAD-mediated transcription can be altered and delayed due to expedited phosphorylation of the linker ofSMAD by TGF-β-activated ERK; and enhanced ERK activity, but attenuated SMAD activity, can be achieved simultaneously by fast turnover ofTGF-β receptors via lipid-rafts. Also, in silico mutations ofthe TGF-β pathways reveal that the dynamic characteristics of both SMAD and ERK signaling may change significantly during cancer development. Specifically, normal cells may exhibit enhanced and sustained SMAD signaling with transient ERK activation, whereas cancerous cells may produce elevated and prolonged ERK signaling with enervated SMAD activation. These distinctive differences between normal and cancerous signaling behavior provide clues concerning, and potential explanations for, the seemingly contradictory roles played by TGF-β during cancer progression. We demonstrate how crosstalk among various branch pathways ofTGF-β can influence overall cellular behavior. Based on model analysis, we hypothesize that aberrant molecular alterations drive changes in the intensity and duration of SMAD and ERK signaling during cancer progression and ultimately lead to an imbalance between the SMAD and ERK pathways in favor of tumor promotion. Thus, to treat cancer patients with a genetic signature of oncogenic Ras effectively may require at least a combination therapy to restore both the expression ofTGF-β receptors and the GTPase activity of Ras.  \nbioRxiv preprint doi: [https://doi.org/10.110","cbCailYW1sSLpGXQ","https://ap.wps.com/l/cbCailYW1sSLpGXQ","pdf",5274823,47,"English","# Abstract\n## Keywords\n## Background","[{\"question\":\"What is the main focus of the computational model in this study?\",\"answer\":\"The study builds an integrated mechanistic model of the TGF-β-triggered ERK activation pathway and analyzes its crosstalk with the SMAD pathway to explain how SMAD dynamics are reshaped by ERK signaling.\"},{\"question\":\"How does ERK signaling affect SMAD-dependent transcription after TGF-β stimulation?\",\"answer\":\"The model indicates that SMAD-mediated transcription can be altered and delayed due to expedited phosphorylation of the SMAD linker by TGF-β-activated ERK.\"},{\"question\":\"What signaling differences does the model predict between normal and cancerous cells?\",\"answer\":\"Normal cells are predicted to show enhanced, sustained SMAD signaling with transient ERK activation, while cancerous cells show elevated, prolonged ERK signaling with attenuated SMAD activity.\"}]","Computational Modeling and Analysis of the TGF-β-induced ERK and SMAD Pathways | PDF",1789993849,118]