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Innovaci\u00f3n","RYC-2016\u201320883","IJC2019\u2013039229-I","CB06\/05\/0041","CB06\/05\/0041"]}]},{"name":"Isabel Gemio Foundation","award":["P18\u201313","Fondo Europeo de Desarrollo Regional","FPU19\/04435","FPU16\/00684","Plan Propio de Iniciaci\u00f3n a la Investigaci\u00f3n, Desarrollo Tecnol\u00f3gico e Innovaci\u00f3n","RYC-2016\u201320883","IJC2019\u2013039229-I","CB06\/05\/0041","CB06\/05\/0041"],"award-info":[{"award-number":["P18\u201313","Fondo Europeo de Desarrollo Regional","FPU19\/04435","FPU16\/00684","Plan Propio de Iniciaci\u00f3n a la Investigaci\u00f3n, Desarrollo Tecnol\u00f3gico e Innovaci\u00f3n","RYC-2016\u201320883","IJC2019\u2013039229-I","CB06\/05\/0041","CB06\/05\/0041"]}]},{"name":"CIBERNED","award":["P18\u201313","Fondo Europeo de Desarrollo Regional","FPU19\/04435","FPU16\/00684","Plan Propio de Iniciaci\u00f3n a la Investigaci\u00f3n, Desarrollo Tecnol\u00f3gico e Innovaci\u00f3n","RYC-2016\u201320883","IJC2019\u2013039229-I","CB06\/05\/0041","CB06\/05\/0041"],"award-info":[{"award-number":["P18\u201313","Fondo Europeo de Desarrollo Regional","FPU19\/04435","FPU16\/00684","Plan Propio de Iniciaci\u00f3n a la Investigaci\u00f3n, Desarrollo Tecnol\u00f3gico e Innovaci\u00f3n","RYC-2016\u201320883","IJC2019\u2013039229-I","CB06\/05\/0041","CB06\/05\/0041"]}]},{"name":"\u201cInstituto de Salud Carlos\u201d III, CIBERNED","award":["P18\u201313","Fondo Europeo de Desarrollo Regional","FPU19\/04435","FPU16\/00684","Plan Propio de Iniciaci\u00f3n a la Investigaci\u00f3n, Desarrollo Tecnol\u00f3gico e Innovaci\u00f3n","RYC-2016\u201320883","IJC2019\u2013039229-I","CB06\/05\/0041","CB06\/05\/0041"],"award-info":[{"award-number":["P18\u201313","Fondo Europeo de Desarrollo Regional","FPU19\/04435","FPU16\/00684","Plan Propio de Iniciaci\u00f3n a la Investigaci\u00f3n, Desarrollo Tecnol\u00f3gico e Innovaci\u00f3n","RYC-2016\u201320883","IJC2019\u2013039229-I","CB06\/05\/0041","CB06\/05\/0041"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease caused by a CTG repeat expansion in the 3\u2032 untranslated region of the dystrophia myotonica protein kinase gene. AKT dephosphorylation and autophagy are associated with DM1. Autophagy has been widely studied in DM1, although the endocytic pathway has not. AKT has a critical role in endocytosis, and its phosphorylation is mediated by the activation of tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR). EGF-activated EGFR triggers the internalization and degradation of ligand\u2013receptor complexes that serve as a PI3K\/AKT signaling platform. Here, we used primary fibroblasts from healthy subjects and DM1 patients. DM1-derived fibroblasts showed increased autophagy flux, with enlarged endosomes and lysosomes. Thereafter, cells were stimulated with a high concentration of EGF to promote EGFR internalization and degradation. Interestingly, EGF binding to EGFR was reduced in DM1 cells and EGFR internalization was also slowed during the early steps of endocytosis. However, EGF-activated EGFR enhanced AKT and ERK1\/2 phosphorylation levels in the DM1-derived fibroblasts. Therefore, there was a delay in EGF-stimulated EGFR endocytosis in DM1 cells; this alteration might be due to the decrease in the binding of EGF to EGFR, and not to a decrease in AKT phosphorylation.<\/jats:p>","DOI":"10.3390\/cells11193018","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T21:23:27Z","timestamp":1664313807000},"page":"3018","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Delay of EGF-Stimulated EGFR Degradation in Myotonic Dystrophy Type 1 (DM1)"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0733-229X","authenticated-orcid":false,"given":"Eva","family":"Alegre-Cort\u00e9s","sequence":"first","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Gen\u00e9tica, Facultad de Enfermer\u00eda y Terapia Ocupacional, Universidad de Extremadura, Avda de la universidad s\/n, 10003 C\u00e1ceres, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Extremadura (INUBE), 06071 C\u00e1ceres, Spain"}]},{"given":"Alberto","family":"Gim\u00e9nez-Bejarano","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Gen\u00e9tica, Facultad de Enfermer\u00eda y Terapia Ocupacional, Universidad de Extremadura, Avda de la universidad s\/n, 10003 C\u00e1ceres, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Extremadura (INUBE), 06071 C\u00e1ceres, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6477-5268","authenticated-orcid":false,"given":"Elisabet","family":"Uribe-Carretero","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Gen\u00e9tica, Facultad de Enfermer\u00eda y Terapia Ocupacional, Universidad de Extremadura, Avda de la universidad s\/n, 10003 C\u00e1ceres, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Extremadura (INUBE), 06071 C\u00e1ceres, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades (CIBERNED), 28031 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5698-8180","authenticated-orcid":false,"given":"Marta","family":"Paredes-Barquero","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Gen\u00e9tica, Facultad de Enfermer\u00eda y Terapia Ocupacional, Universidad de Extremadura, Avda de la universidad s\/n, 10003 C\u00e1ceres, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Extremadura (INUBE), 06071 C\u00e1ceres, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9674-3017","authenticated-orcid":false,"given":"Andr\u00e9 R. A.","family":"Marques","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas, NMS|FCM, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal"}]},{"given":"Mafalda","family":"Lopes-da-Silva","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas, NMS|FCM, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4924-1780","authenticated-orcid":false,"given":"Ot\u00edlia V.","family":"Vieira","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas, NMS|FCM, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal"}]},{"given":"Saray","family":"Canales-Cort\u00e9s","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Gen\u00e9tica, Facultad de Enfermer\u00eda y Terapia Ocupacional, Universidad de Extremadura, Avda de la universidad s\/n, 10003 C\u00e1ceres, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Extremadura (INUBE), 06071 C\u00e1ceres, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5026-7166","authenticated-orcid":false,"given":"Pedro J.","family":"Camello","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Veterinaria, Universidad de Extremadura, 10003 C\u00e1ceres, Spain"},{"name":"Instituto Universitario de Biomarcadores de Patolog\u00edas Metab\u00f3licas, 10003 C\u00e1ceres, Spain"}]},{"given":"Guadalupe","family":"Mart\u00ednez-Chac\u00f3n","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Gen\u00e9tica, Facultad de Enfermer\u00eda y Terapia Ocupacional, Universidad de Extremadura, Avda de la universidad s\/n, 10003 C\u00e1ceres, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Extremadura (INUBE), 06071 C\u00e1ceres, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades (CIBERNED), 28031 Madrid, Spain"}]},{"given":"Ana","family":"Aiastui","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades (CIBERNED), 28031 Madrid, Spain"},{"name":"Cell Culture Platform, Biodonostia Health Research Institute, 20014 San Sebasti\u00e1n, Spain"},{"name":"Neuroscience Area of Biodonostia Health Research Institute, Donostia University Hospital, 20014 San Sebasti\u00e1n, Spain"}]},{"given":"Roberto","family":"Fern\u00e1ndez-Torr\u00f3n","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades (CIBERNED), 28031 Madrid, Spain"},{"name":"Neuroscience Area of Biodonostia Health Research Institute, Donostia University Hospital, 20014 San Sebasti\u00e1n, Spain"},{"name":"Department of Neurology, Donostia University Hospital, 20014 Osakidetza, Spain"},{"name":"Ilundain Foundation, 20014 San Sebastian, Spain"},{"name":"Department of Neurosciences, University of the Basque Country UPV-EHU, 48940 San Sebasti\u00e1n, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9509-4032","authenticated-orcid":false,"given":"Adolfo","family":"L\u00f3pez de Munain","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades (CIBERNED), 28031 Madrid, Spain"},{"name":"Neuroscience Area of Biodonostia Health Research Institute, Donostia University Hospital, 20014 San Sebasti\u00e1n, Spain"},{"name":"Department of Neurology, Donostia University Hospital, 20014 Osakidetza, Spain"},{"name":"Ilundain Foundation, 20014 San Sebastian, Spain"},{"name":"Department of Neurosciences, University of the Basque Country UPV-EHU, 48940 San Sebasti\u00e1n, Spain"}]},{"given":"Patricia","family":"Gomez-Suaga","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Gen\u00e9tica, Facultad de Enfermer\u00eda y Terapia Ocupacional, Universidad de Extremadura, Avda de la universidad s\/n, 10003 C\u00e1ceres, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Extremadura (INUBE), 06071 C\u00e1ceres, Spain"}]},{"given":"Mireia","family":"Niso-Santano","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Gen\u00e9tica, Facultad de Enfermer\u00eda y Terapia Ocupacional, Universidad de Extremadura, Avda de la universidad s\/n, 10003 C\u00e1ceres, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Extremadura (INUBE), 06071 C\u00e1ceres, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades (CIBERNED), 28031 Madrid, Spain"}]},{"given":"Rosa A.","family":"Gonz\u00e1lez-Polo","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Gen\u00e9tica, Facultad de Enfermer\u00eda y Terapia Ocupacional, Universidad de Extremadura, Avda de la universidad s\/n, 10003 C\u00e1ceres, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Extremadura (INUBE), 06071 C\u00e1ceres, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades (CIBERNED), 28031 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6910-2089","authenticated-orcid":false,"given":"Jos\u00e9 M.","family":"Fuentes","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Gen\u00e9tica, Facultad de Enfermer\u00eda y Terapia Ocupacional, Universidad de Extremadura, Avda de la universidad s\/n, 10003 C\u00e1ceres, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Extremadura (INUBE), 06071 C\u00e1ceres, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades (CIBERNED), 28031 Madrid, Spain"}]},{"given":"Sokhna M. S.","family":"Yakhine-Diop","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Extremadura (INUBE), 06071 C\u00e1ceres, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades (CIBERNED), 28031 Madrid, Spain"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1080\/13510002.2015.1107311","article-title":"Redox imbalance in peripheral blood of type 1 myotonic dystrophy patients","volume":"21","author":"Marinkovic","year":"2016","journal-title":"Redox Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1159\/000369343","article-title":"Prevalence of muscular dystrophies: A systematic literature review","volume":"43","author":"Theadom","year":"2014","journal-title":"Neuroepidemiology"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Dogan, C., De Antonio, M., Hamroun, D., Varet, H., Fabbro, M., Rougier, F., Amarof, K., Arne Bes, M.C., Bedat-Millet, A.L., and Behin, A. (2016). Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0148264"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1111\/ene.13763","article-title":"Survival patterns and cancer determinants in families with myotonic dystrophy type 1","volume":"26","author":"Best","year":"2019","journal-title":"Eur. J. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1242\/dmm.018127","article-title":"Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model","volume":"8","author":"Bargiela","year":"2015","journal-title":"Dis. Models Mech."},{"key":"ref_6","first-page":"1763","article-title":"mTOR-dependent proliferation defect in human ES-derived neural stem cells affected by myotonic dystrophy type 1","volume":"126","author":"Denis","year":"2013","journal-title":"J. Cell Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1038\/cdd.2010.33","article-title":"Normal myogenesis and increased apoptosis in myotonic dystrophy type-1 muscle cells","volume":"17","author":"Loro","year":"2010","journal-title":"Cell Death Differ."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2789","DOI":"10.1093\/hmg\/ddy192","article-title":"Mechanisms of skeletal muscle wasting in a mouse model for myotonic dystrophy type 1","volume":"27","author":"Morriss","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1172\/JCI89616","article-title":"Targeting deregulated AMPK\/mTORC1 pathways improves muscle function in myotonic dystrophy type I","volume":"127","author":"Brockhoff","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1038\/ncb1101-1014","article-title":"Akt\/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo","volume":"3","author":"Bodine","year":"2001","journal-title":"Nat. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.3892\/ijo.2015.2871","article-title":"EGFstimulated AKT activation is mediated by EGFR recycling via an early endocytic pathway in a gefitinibresistant human lung cancer cell line","volume":"46","author":"Nishimura","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"ra45","DOI":"10.1126\/scisignal.2004015","article-title":"AKT facilitates EGFR trafficking and degradation by phosphorylating and activating PIKfyve","volume":"6","author":"Er","year":"2013","journal-title":"Sci. Signal."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.devcel.2008.06.012","article-title":"Clathrin-mediated internalization is essential for sustained EGFR signaling but dispensable for degradation","volume":"15","author":"Sigismund","year":"2008","journal-title":"Dev. 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