{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T08:41:35Z","timestamp":1792312895366,"version":"4.4.0"},"reference-count":126,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T00:00:00Z","timestamp":1695168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Comunidad de Madrid","award":["P2022\/BMD-7321"],"award-info":[{"award-number":["P2022\/BMD-7321"]}]},{"name":"ProACapital","award":["P2022\/BMD-7321"],"award-info":[{"award-number":["P2022\/BMD-7321"]}]},{"name":"HALE KULANI, S. L.","award":["P2022\/BMD-7321"],"award-info":[{"award-number":["P2022\/BMD-7321"]}]},{"name":"MJR","award":["P2022\/BMD-7321"],"award-info":[{"award-number":["P2022\/BMD-7321"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The IRS (insulin receptor substrate) family of scaffold proteins includes insulin receptor substrate-4 (IRS4), which is expressed only in a few cell lines, including human kidney, brain, liver, and thymus and some cell lines. Its N-terminus carries a phosphotyrosine-binding (PTB) domain and a pleckstrin homology domain (PH), which distinguishes it as a member of this family. In this paper, we collected data about the molecular mechanisms that explain the relevance of IRS4 in the development of cancer and identify IRS4 differences that distinguish it from IRS1 and IRS2. Search engines and different databases, such as PubMed, UniProt, ENSEMBL and SCANSITE 4.0, were used. We used the name of the protein that it encodes \u201c(IRS-4 or IRS4)\u201d, or the combination of these terms with the word \u201c(cancer)\u201d or \u201c(human)\u201d, for searches. Terms related to specific tumor pathologies (\u201cbreast\u201d, \u201covary\u201d, \u201ccolon\u201d, \u201clung\u201d, \u201clymphoma\u201d, etc.) were also used. Despite the lack of knowledge on IRS4, it has been reported that some cancers and benign tumors are characterized by high levels of IRS-4 expression. Specifically, the role of IRS-4 in different types of digestive tract neoplasms, gynecological tumors, lung cancers, melanomas, hematological tumors, and other less common types of cancers has been shown. IRS4 differs from IRS1 and IRS2 in that can activate several oncogenes that regulate the PI3K\/Akt cascade, such as BRK and FER, which are characterized by tyrosine kinase-like activity without regulation via extracellular ligands. In addition, IRS4 can activate the CRKL oncogene, which is an adapter protein that regulates the MAP kinase cascade. Knowledge of the role played by IRS4 in cancers at the molecular level, specifically as a platform for oncogenes, may enable the identification and validation of new therapeutic targets.<\/jats:p>","DOI":"10.3390\/cancers15184651","type":"journal-article","created":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T21:47:03Z","timestamp":1695246423000},"page":"4651","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Is Insulin Receptor Substrate4 (IRS4) a Platform Involved in the Activation of Several Oncogenes?"],"prefix":"10.3390","volume":"15","author":[{"given":"Luis G.","family":"Guijarro","sequence":"first","affiliation":[{"name":"Unit of Biochemistry and Molecular Biology, Department of System Biology (CIBEREHD), University of Alcal\u00e1, 28801 Alcala de Henares, Spain"},{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Javier","family":"Justo Bermejo","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Biotechnology, University of Alcal\u00e1, 28801 Alcala de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego Liviu","family":"Boaru","sequence":"additional","affiliation":[{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"},{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcala de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"De Castro-Martinez","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcala de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"De Leon-Oliva","sequence":"additional","affiliation":[{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"},{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcala de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4494-6397","authenticated-orcid":false,"given":"Oscar","family":"Fraile-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"},{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcala de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6016-7855","authenticated-orcid":false,"given":"Cielo","family":"Garcia-Montero","sequence":"additional","affiliation":[{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"},{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcala de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1309-7510","authenticated-orcid":false,"given":"Melchor","family":"Alvarez-Mon","sequence":"additional","affiliation":[{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"},{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcala de Henares, Spain"},{"name":"Immune System Diseases-Rheumatology, Oncology Service and Internal Medicine (CIBEREHD), University Hospital Pr\u00edncipe de Asturias, 28806 Alcala de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7222-8096","authenticated-orcid":false,"given":"Mar\u00eda del Val","family":"Toledo-Lobo","sequence":"additional","affiliation":[{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"},{"name":"Department of Biomedicine and Biotechnology, University of Alcal\u00e1, 28801 Alcala de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2588-1708","authenticated-orcid":false,"given":"Miguel A.","family":"Ortega","sequence":"additional","affiliation":[{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"},{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcala de Henares, Spain"},{"name":"Cancer Registry and Pathology Department, Principe de Asturias University Hospital, 28806 Alcala de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1478-811X-7-14","article-title":"Expression and function of the insulin receptor substrate proteins in cancer","volume":"7","author":"Mardilovich","year":"2009","journal-title":"Cell Commun. 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