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 “(IRS-4 or IRS4)”, or the combination of these terms with the word “(cancer)” or “(human)”, for searches. Terms related to specific tumor pathologies (“breast”, “ovary”, “colon”, “lung”, “lymphoma”, 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.
胰岛素受体底物（IRS）支架蛋白家族成员包括胰岛素受体底物-4（IRS4），该蛋白仅表达于少数细胞系中，包括人类肾脏、脑、肝脏、胸腺及部分细胞系。其N端携带磷酸酪氨酸结合结构域（PTB）和普列克底物蛋白同源结构域（PH），这一特征使其成为该家族的标志性成员。本文通过整合数据，系统阐述了IRS4在癌症发生发展中的分子机制，并明确了IRS4区别于IRS1和IRS2的特征差异。研究采用PubMed、UniProt、ENSEMBL及SCANSITE 4.0等搜索引擎与数据库，以编码蛋白名称“（IRS-4或IRS4）”及其与“（癌症）”或“（人类）”的组合词进行检索，同时结合特定肿瘤病理学相关术语（如“乳腺”“卵巢”“结肠”“肺”“淋巴瘤”等）。尽管目前对IRS4的认知尚不充分，但已有研究报道某些癌症与良性肿瘤以高表达IRS-4为特征。具体而言，IRS4在消化道肿瘤、妇科肿瘤、肺癌、黑色素瘤、血液系统肿瘤及其他罕见癌症类型中的作用已被揭示。IRS4与IRS1、IRS2的核心差异在于其能激活多个调控PI3K/Akt信号通路的致癌基因，例如具有酪氨酸激酶样活性且不受细胞外配体调控的BRK与FER。此外，IRS4还能激活CRKL致癌基因——该基因作为衔接蛋白参与调控MAP激酶级联反应。从分子层面深入解析IRS4在癌症中的作用机制，特别是其作为致癌基因平台的功能，有望为新型治疗靶点的发现与验证提供关键理论依据。
Is Insulin Receptor Substrate4 (IRS4) a Platform Involved in the Activation of Several Oncogenes?
肿瘤(癌症)患者之家