Batkulwar Kedar B, Bansode Sneha B, Patil Gouri V, Godbole Rashmi K, Kazi Rubina S, Chinnathambi Subashchandrabose, Shanmugam Dhanasekaran, Kulkarni Mahesh J
Proteomics Facility, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Pune, India.
Proteomics. 2015 Jan;15(2-3):245-59. doi: 10.1002/pmic.201400169. Epub 2014 Dec 17.
The receptor for advanced glycation end products (RAGE) is one of the most important proteins implicated in diabetes, cardiovascular diseases, neurodegenerative diseases, and cancer. It is a pattern recognition receptor by virtue of its ability to interact with multiple ligands, RAGE activates several signal transduction pathways through involvement of various kinases that phosphorylate their respective substrates. Only few substrates have been known to be phosphorylated in response to activation by RAGE (e.g., nuclear factor kappa B); however, it is possible that these kinases can phosphorylate multiple substrates depending upon their expression and localization, leading to altered cellular responses in different cell types and conditions. One such example is, glycogen synthase kinase 3 beta which is known to phosphorylate glycogen synthase, acts downstream to RAGE, and hyperphosphorylates microtubule-associated protein tau causing neuronal damage. Thus, it is important to understand the role of various RAGE-activated kinases and their substrates. Therefore, we have reviewed here the details of RAGE-activated kinases in response to different ligands and their respective phosphoproteome. Furthermore, we discuss the analysis of the data mined for known substrates of these kinases from the PhosphoSitePlus (http://www.phosphosite.org) database, and the role of some of the important substrates involved in cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases. In summary, this review provides information on RAGE-activated kinases and their phosphoproteome, which will be helpful in understanding the possible role of RAGE and its ligands in progression of diseases.
晚期糖基化终产物受体（RAGE）是与糖尿病、心血管疾病、神经退行性疾病和癌症相关的最重要蛋白质之一。凭借其与多种配体相互作用的能力，它是一种模式识别受体，RAGE通过多种激酶的参与激活多种信号转导途径，这些激酶会磷酸化各自的底物。已知只有少数底物会因RAGE激活而被磷酸化（例如，核因子κB）；然而，根据它们的表达和定位，这些激酶有可能磷酸化多种底物，从而导致不同细胞类型和条件下细胞反应的改变。一个这样的例子是糖原合酶激酶3β，它已知会磷酸化糖原合酶，在RAGE下游起作用，并使微管相关蛋白tau过度磷酸化，导致神经元损伤。因此，了解各种RAGE激活的激酶及其底物的作用很重要。因此，我们在此回顾了RAGE激活的激酶对不同配体的反应及其各自的磷酸化蛋白质组的详细情况。此外，我们讨论了从PhosphoSitePlus（http://www.phosphosite.org）数据库挖掘这些激酶已知底物的数据的分析，以及一些参与癌症、糖尿病、心血管疾病和神经退行性疾病的重要底物的作用。总之，本综述提供了有关RAGE激活的激酶及其磷酸化蛋白质组的信息，这将有助于理解RAGE及其配体在疾病进展中的可能作用。
