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. 2021 Jul 6;18(14):7236. doi: 10.3390/ijerph18147236

Figure 2.

Figure 2

Signaling pathways induced by the activation of the receptor of AGEs. (a) RAGE is a cell surface receptor composed of three extracellular domains, a transmembrane domain, and a short cytoplasmic tail. (b) AGEs bind to RAGE’s extracellular portion and induce activation of the cytoplasmic domain, leading to different signaling pathways, which will finally result in the stimulation of transcription factors such as NF-KB and ISRE. Three pathways that can lead to such a response: (c) activation of the protein p21, which induces RAF-1, MEKK-1, and MEK 3/6 proteins that activate the factors ERK, JNK, and MAPK, which translocate to the cell nucleus. (d) Activation of the JAK2/STAT1 pathway, where STAT1 dimerizes and binds to the IRF1 sequence to translocate to the cell nucleus, binding to the ISRE segment and inducing transcription of proinflammatory cytokines. (e) Activation of the NADPH oxidase that leads to the stimulation of NF-KB. These processes can be activated by other molecules such as S100, Mac-1, HMBG-1, and β-amyloids. NF-kB: nuclear factor kappa light chain enhancer of activated B cells, ISRE: interferon-sensitive response element, TNFα: tumor necrosis factor-alpha, IL: interleukins, VCAM-1: adherence and growth factors as the vascular cell adhesion molecule-1, TGF-β1: transforming growth factor β, RAF-1: proto-oncogene serine/threonine kinase, MEKK-1: mitogen-activated protein kinase kinase kinase 1, MEK 3/6: mitogen-activated protein kinase kinase, ERK: extracellular signal-regulated kinase, JNK: c-Jun N-terminal kinase, MAPK: mitogen-activated protein kinase, JAK: Janus kinase, STAT: signal transducer and activators of transcription, IRF1: interferon regulatory factor-1, S 100: calgranulin, and HMBG1: high-mobility group box 1.