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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The MAPK signaling pathway (also known as the RAS-RAF-MEK-ERK pathway) is a chain of proteins in cells that communicate a signal from a receptor on the surface of the cell to the DNA in the nucleus. The pathway includes many proteins, including MAPK (Mitogen-Activated Protein Kinases), originally called ERKs (Extracellular signal-Regulated Kinases), which communicate by adding phosphate groups to neighboring proteins (i.e., phosphorylating them), which acts as a series of “on” or “off” switches. The process starts when a signaling molecule binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein, producing some change in the cell such as cell division (Figure 6.42). Diagram illustrating the MAPK signaling pathway (Taken from Wikipedia, “MAPK pathway schematic” by Fred the Oyster, under the Creative Commons Attribution-Share Alike 4.0 International license (https://creativecommons.org/licenses/by-sa/4.0/legalcode)).
Adaptive Resistance Mechanisms in EGFR Mutant NSCLC
Published in Il-Jin Kim, Companion Diagnostics (CDx) in Precision Medicine, 2019
Mariacarmela Santarpia, Niki Karachaliou, Martyna Filipska, Clara Mayo-de-las-Casas, Chiara Lazzari, Maria González-Cao, Rafael Rosell
The RAS/RAF/MEK/ERK (or RAS/RAF/mitogen-activated protein kinase, MAPK) signaling cascade is widely activated by a variety of RTKs, including EGFR, and is involved in regulating pleiotropic cellular functions. Extracellular signal-regulated kinase-1 (ERK1) and ERK2A play a major role in the pathway through phosphorylation of downstream mediators involved in cell proliferation, differentiation and survival. A complex network of negative-feedback interactions limits the amplitude and duration of ERK signaling. In a recent study performed on EGFR mutant NSCLC cell models, prolonged erlotinib treatment for 24–48 h produced a rebound in ERK phosphorylation, as was also observed with irreversible EGFR TKIs, afatinib and neratinib (Ma et al., 2016). Phospho-ERK rebound was significantly attenuated by concomitant administration of erlotinib and a MEK inhibitor, trametinib. The MAPK feedback reactivation was further demonstrated to be dependent on MET receptor activation. Interestingly, residual cells after initial erlotinib treatment due to adaptive resistance promoted the development of cell subclones with acquired resistance after long-term treatment with erlotinib, thus suggesting MAPK pathway reactivation triggered by erlotinib may be involved in both mechanisms of resistance and concomitant triggering of EGFR and MAPK could represent a promising therapeutic synergistic approach to inhibit or delay the occurrence of resistance.
Precision medicine for colorectal cancer
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Candan Hızel, Şükrü Tüzmen, Arsalan Amirfallah, Gizem Çalıbaşı Koçal, Duygu Abbasoğlu, Haluk Onat, Yeşim Yıldırım, Yasemin Baskın
Mitogen-activated protein kinase (MAPK) cascades are key signaling pathways involved in the regulation of normal cell proliferation, survival, and differentiation. Dysregulation of MAPK cascades contribute to cancer development. Four distinct MAPK cascades have been identified. They are called extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), p38, and ERK5. Each of them is composed of three sequentially acting kinases, activating one after the other (MAPKKK/MAP3K, MAPKK/MAP2K, and MAPK) (Thompson and Lyons, 2005).
Sirtuins as therapeutic targets for improving delayed wound healing in diabetes
Published in Journal of Drug Targeting, 2022
Fathima Beegum, Anuranjana P. V., Krupa Thankam George, Divya K. P., Farmiza Begum, Nandakumar Krishnadas, Rekha R. Shenoy
The role of SIRT 1 in other diabetic complications was also emphasised. Resveratrol was found to be effective in diabetic foot syndrome through SIRT 1 activation and tissue regeneration [105]. It increased the endothelial cell proliferation by activating the ERK signalling pathway and improved cutaneous wound healing [105]. Extracellular signal regulated kinase (ERK) signalling pathway is one of the major signalling cascades of mitogen activated protein kinase signalling pathway. The activation of ERK by SIRT 1 phosphorylates ribosomal S6 kinase (RSK) and ERK translocates to the nucleus where they activate transcription factors including CREB, Fos proto-oncogene (FOS), ETS domain containing protein (Elk-1) eventually resulting in effector protein synthesis causing changes in cell proliferation and survival. CREB, being a cellular transcription factor can enhance gene transcription for above ten times. c-Fos, 380 amino acid protein with basic leucine zipper region for dimerisation and DNA binding and a transactivation domain at C-terminus, is involved in cell proliferation, differentiation and survival. Elk-1 is a protein that is encoded in humans by ELK-1 gene, function as transcription activator. As a result of the activation of SIRT-1, there is enhanced cellular proliferation and improved cutaneous wound healing. The polymer-based sponge loaded with chitosan sodium hyaluronate-resveratrol stimulates tissue regeneration and formation of granulation tissue to facilitate healing of wounds [106].
A review of protein-protein interaction and signaling pathway of Vimentin in cell regulation, morphology and cell differentiation in normal cells
Published in Journal of Receptors and Signal Transduction, 2022
Danial Hashemi Karoii, Hossein Azizi
The extracellular signal-regulated kinase (Erk) route, which is often up-regulated in many malignancies and is involved in numerous cellular activities, including proliferation and motility, is a carcinogenesis pathway involving Vimentin [63]. Cleavage fragments of synthesized vimentin were recently shown to bind with phosphorylated Erk1 and Erk2 MAP kinases (pErk) in the injured sciatic nerve, linking pErk to a signaling pathway complex transported retrogradely on importins and dynein. According to Perlson et al., vimentin binding to pErk occludes the lip of the kinase containing the phosphorylated residues. Binding competition tests with Erk peptides demonstrated that vimentin covers the phosphorylation lip in pErk and interacts with residues above and below the lip. The same peptides blocked pErk binding to the dynein complex in sciatic nerve axoplasm and interfered with vimentin’s protection from phosphatases. As a result of calcium-dependent steric hindrance, a soluble intermediate filament fragment binds with a signaling kinase and protects it from dephosphorylation [61,64].
Glutathione Trisulfide Prevents Lipopolysaccharide-induced Inflammatory Gene Expression in Retinal Pigment Epithelial Cells
Published in Ocular Immunology and Inflammation, 2022
Hiroshi Tawarayama, Noriyuki Suzuki, Maki Inoue-Yanagimachi, Noriko Himori, Satoru Tsuda, Kota Sato, Tomoaki Ida, Takaaki Akaike, Hiroshi Kunikata, Toru Nakazawa
ARPE-19 cells, as well as human and mouse primary RPE cells, were maintained and expanded in 10-cm dishes containing the appropriate medium per cell type (described above) in a 5% CO2 incubator at 37°C. One day before the experiments, 1 × 104 cells/well were seeded in 96-well culture plates. The next day, the wells became roughly 50–70% confluent. ARPE-19 cells and human and mouse primary RPE cells were pretreated with GSSSG or GSSG for 1 h. Subsequently, 10, 1, or 0.1 µg/ml of LPS (Sigma-Aldrich, St. Louis, MO, USA) was added into these glutathione-containing cultures, respectively, and the cells were incubated for 6 more hours to induce the expression of inflammatory genes. The same concentration of LPS was reportedly used to induce acute inflammation responses in ARPE-19 and primary RPE cells.35–41 In some experiments, cells were pretreated with the extracellular signal-regulated kinase (ERK) inhibitor FR180204 (Santa Cruz Biotechnology, Dallas, TX, USA) and activator C6-ceramide (Santa Cruz Biotechnology) for 1 h before treatment with GSSSG.