AGE/RAGE pathway

Advanced glycation end products (AGEs) are heterogeneous group of non-enzymatic malliard reaction products of aldose sugar with proteins and lipids. Formation of AGEs is an indicator of one of the many chemical modifications of proteins and DNA that occur within the biological systems. Research over past two decades have implicated the role of AGEs in most of the age-related diseases like Alzheimer's disease, cancer, cardiovascular disease, diabetes, renal disorders, hypertension, stroke, visual impairment and skin disorders. AGEs also modify the skin collagen and accelerates the aging process. In diabetic patients, AGE formation occurs in large scale and manifests with clinical symptoms such as cataract, atherosclerosis, nephropathy and neuropathy. AGEs are known to bind with different cell surface receptors such as receptor for advanced glycation end products (RAGE), dolichyldiphosphooligosaccharide-protein glycosyltransferase (AGE-R1), protein kinase C substrate, 80KH phosphoprotein (AGE-R2), galectin-3 (AGE-R3), and class A macrophage scavenger receptor types I and II. RAGE, is the well-studied receptor for AGEs and the signaling events mediated by others are either not been identified or are considered as negative regulators of RAGE signaling. RAGE is an integral membrane protein of the immunoglobulin superfamily. RAGE is constituted of an extracellular domain, a transmembrane domain and a short cytoplasmic domain. RAGE is expressed in a wide range of tissues such as lung, heart, kidney, brain, skeletal muscles, and in different types of cells including endothelial cells, macrophages/monocytes, neutrophils, and lymphocytes. Besides AGEs, RAGE also mediate the effects of its other extracellular ligands namely extracellular high mobility group box-1 (HMGB1), S100 family of calcium binding proteins and amyloid-beta peptide, among many others. Although a large number of advanced glycation end products have been identified in humans, AGE/RAGE signaling ex-vivo is mostly studied using the AGEs such as AGE-modified albumin, N(6)(carboxymethyl)lysine, N(6)(carboxyethyl)lysine and pentosidine. The signaling events mediated by RAGE are complex due to the diversity of its ligands and their effects in different cell types. Homodimerization of RAGE has been identified to be essential for RAGE signaling. Depending on the intensity and duration of RAGE ligation, specific signaling modules such as ERK1/2, p38 MAPK, CDC42/RAC, SAPK/JNK and NF-κB has been shown to be regulated in different cell types. AGEs have been shown to induce the formation of complexes containing RAGE with DIAPH1, SRC/IRS1/PKC-alpha, TIRAP/MYD88/IRAK4 and RHOA. RAGE-DIAPH1 interaction is required for the activation of RAC1/CDC42 pathway leading to neurite outgrowth and regulation of cytoskeleton.Activation of PKC-alpha through RAGE/SRC/IRS1/PKC-alpha by AGEs has been suggested as a mechanism of insulin resistance in skeletal muscle cells. RAGE also shares the adaptor molecules such as TIRAP, MYD88 and IRAK4 of toll-like receptors and induce the activation of AKT, p38MAPK and NFKB pathways. AGEs have also been shown to induce the formation of complex between RAGE and RHOA. RHOA/ROCK dependent phosphorylation of ezrin/radixin/moesin (ERM) is required for the regulation of gap formation and actin reorganization, and thereby endothelial permeability. However, in tubular cells, AGEs inhibit phosphorylation of ERMs leading to inhibition of tubulogenesis. Similarly, AKT have been shown to be activated by AGEs and induce proliferation of primary acute myeloid leukemia (AML) cells where as phosphorylation of AKT is shown to be inhibited in podocytes leading to FOXO4 activation and apoptosis. The major component of AGE/RAGE signaling is the oxidative stress induced pathways. AGEs induce the oxidative stress through the activation of NADPH oxidases. Increased intracellular oxidative stress leads to stimulation of PKC and ERK1/2, resulting in the translocation and activation of NF-κB and subsequent up regulation of NF-κB dependent genes which ultimately produce deleterious effects to cells. Please access this pathway at [http://www.netpath.org/netslim/age_signaling_pathways.html NetSlim] database. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP2324 CPTAC Assay Portal]

高级糖基化终产物（AGEs）是由醛糖糖与蛋白质和脂质发生非酶促美拉德反应产生的一组异质非酶促反应产物。AGEs的形成是生物系统中蛋白质和DNA发生多种化学修饰之一的重要标志。在过去二十年的研究中，AGEs在大多数与年龄相关的疾病，如阿尔茨海默病、癌症、心血管疾病、糖尿病、肾脏疾病、高血压、中风、视力障碍和皮肤病中的作用已被提及。AGEs还会改变皮肤胶原蛋白并加速衰老过程。在糖尿病患者中，AGEs的形成规模较大，并伴有白内障、动脉粥样硬化、肾病和神经病变等临床症状。AGEs已知可以与不同的细胞表面受体结合，如晚期糖基化终产物受体（RAGE）、多聚糖蛋白甘露糖基转移酶（AGE-R1）、蛋白激酶C底物、80KH磷酸蛋白（AGE-R2）、半乳糖凝集素-3（AGE-R3）和A类巨噬细胞清道夫受体I型和II型。RAGE是AGEs研究最为深入的受体，而由其他受体介导的信号事件尚未被识别或被视为RAGE信号通路的负调节因子。RAGE是免疫球蛋白超家族的膜蛋白，由细胞外结构域、跨膜结构域和短细胞内结构域组成。RAGE在肺、心、肾、脑、骨骼肌等广泛组织以及内皮细胞、巨噬细胞/单核细胞、中性粒细胞和淋巴细胞等多种细胞类型中表达。除了AGEs外，RAGE还介导其其他细胞外配体（如细胞外高迁移率族蛋白1（HMGB1）、钙结合蛋白S100家族和淀粉样蛋白-β肽等）的效果。尽管在人类中已鉴定出大量高级糖基化终产物，但AGE/RAGE信号通路体外研究主要使用AGEs，如AGE修饰的人血清白蛋白、N(6)(羧甲基)赖氨酸、N(6)(羧乙基)赖氨酸和戊糖胺。由RAGE介导的信号事件复杂，由于其配体的多样性和它们在不同细胞类型中的效应。已确定RAGE的同源二聚化对于RAGE信号通路至关重要。根据RAGE交联的强度和持续时间，不同的信号模块，如ERK1/2、p38 MAPK、CDC42/RAC、SAPK/JNK和NF-κB，在不同细胞类型中被证明受到调节。AGEs已被证明可以诱导包含RAGE与DIAPH1、SRC/IRS1/PKC-α、TIRAP/MYD88/IRAK4和RHOA的复合物形成。RAGE-DIAPH1相互作用对于激活RAC1/CDC42通路、导致神经突生长和细胞骨架的调节是必需的。AGEs通过RAGE/SRC/IRS1/PKC-α激活PKC-α的机制已被提出，可能是骨骼肌细胞胰岛素抵抗的机制。RAGE还共享了TLR的适配分子，如TIRAP、MYD88和IRAK4，并诱导AKT、p38MAPK和NFKB通路的激活。AGEs还已被证明可以诱导RAGE和RHOA之间的复合物形成。RHOA/ROCK依赖的ezrin/radixin/moesin（ERM）磷酸化对于调节间隙形成和肌动蛋白重组、从而调节内皮通透性是必需的。然而，在管状细胞中，AGEs抑制ERM的磷酸化，导致管化作用抑制。类似地，AKT已被证明可以被AGEs激活，并诱导原代急性髓系白血病（AML）细胞的增殖，而AKT的磷酸化已被证明在足细胞中被抑制，导致FOXO4的激活和细胞凋亡。AGE/RAGE信号通路的主要成分是氧化应激诱导的通路。AGEs通过激活NADPH氧化酶诱导氧化应激。细胞内氧化应激的增加导致PKC和ERK1/2的刺激，从而引起NF-κB的转位和激活以及随后的NF-κB依赖性基因的上调，最终对细胞产生有害影响。请访问[http://www.netpath.org/netslim/age_signaling_pathways.html NetSlim]数据库获取此通路信息。该通路上的蛋白质可通过[https://assays.cancer.gov/available_assays?wp_id=WP2324 CPTAC检测门户]进行靶向检测。