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Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
RET is another receptor tyrosine kinase, encoded by the RET gene. It is believed to be required for development of the kidneys and enteric system, as well as for the differentiation and survival of neurons [71, 72]. The ligand for RET receptors are glial-derived neurotrophic factor (GDNF) family of neurotrophins, which include neurturin (NTN), artemin (ART) and persephin (PSP) [72]. After ligand binding, the intracellular kinase domain is activated, followed by autophosphorylation of intracellular tyrosine residues. These phospho-tyrosine residues then serve as platform where downstream signaling proteins carrying SRC homology 2 (SH2) or phosphotyrosine-binding (PTB) domains bind and transmit signals into the cell, leading to the activation of RAS/ERK1/2 and PI3K/AKT pathways [73]. Rearrangements in RET gene result in formation of fusion proteins (with the tyrosine kinase domain of Ret receptor) which are capable of undergoing constitutive dimerization leading to subsequent ligand independent kinase activation, potentially resulting in neoplastic transformation [72]. Although data from in vitro and xenograft models support the potential of RET inhibitors in the treatment of RET fusion-positive NSCLC, information about mechanisms by which these oncogenic fusion proteins exert their transforming action is lacking [73].
Multiple Endocrine Neoplasia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The RET (rearranged during transfection) gene on chromosome 10q11.21 spans 53 kb with 21 exons and encodes a 1,114 aa, 124 kDa protein (transmembrane tyrosine kinase), which is composed of an extracellular portion (including signal peptide, cadherin-like domain, and cysteine-rich region), a single transmembrane region, and an intracellular portion (including two tyrosine kinase domains, TK1 and TK2). Interaction with ligands such as glial cell line-derived neurotrophic factor (GDNF), neurturin (TNT), artemin, or persephin stimulates RET dimerization, cross-autophosphorylation, and subsequent phosphorylation of intracellular substrates, leading to activation of downstream signaling pathways involved in cell differentiation, growth, migration, and survival [10].
Biotherapeutic effect of cell-penetrating peptides against microbial agents: a review
Published in Tissue Barriers, 2022
Idris Zubairu Sadiq, Aliyu Muhammad, Sanusi Bello Mada, Bashiru Ibrahim, Umar Aliyu Umar
Protein-derived peptides are peptides that are often derived from proteins, which may originate from natural sources such as plants, animals, or microorganisms (bacteria, yeast, and fungi). These protein-derived peptides are usually obtained from enzyme hydrolysis, fermentation, or digestion.19 Hydrolytic enzymes are commonly used to digest these proteins from a variety of sources, after which the bioactivity of the entire crude extract is assessed, followed by a series of activity-guided purification and identification to determine the most appropriate sequence.15,20 A peptide generated from the prion protein with a hydrophobic sequence was demonstrated to have powerful antiprion effects in prion-infected cells by reducing the pathogenic scrapie isoform crucial for prion pathogenicity.21 A research utilized both an in silico and an experimental technique to find protein-derived CPPs by extracting arginine-rich peptide segments from SwissProt proteins and analyzing their cell-penetrating capabilities.22 A study revealed multiple unique human-protein-derived CPPs employing a combination of in silico and experimental methods. Twenty of the sixty peptides tested were found to be functional, with the neurturin peptide performing best across the peptides screened.23
The preclinical discovery and development of opicapone for the treatment of Parkinson’s disease
Published in Expert Opinion on Drug Discovery, 2020
Miren Ettcheto, Oriol Busquets, Elena Sánchez-Lopez, Amanda Cano, Patricia R. Manzine, Ester Verdaguer, Jordi Olloquequi, Carme Auladell, Jaume Folch, Antoni Camins
Another strategy used to modify or delay the disease has been the use of neurotrophic growth factors such as glial cell-line-derived neurotrophic factor (GDNF) and neurturin (NTN), which are members of the transforming growth factor β superfamily [85]. The objective of these strategies is to restore the viability of degenerated neurons. A clinical trial (ClinicalTrials.gov, number NCT00985517) has been conducted based on the direct administration of the gene therapy of an AAV2-neurturin vector (CERE-120) in the brain (to the putamen plus substantia nigra) [85–87]. However, the phase 2 was discontinued because the compound did not demonstrate statistically significant efficacy for an improvement in patient scores according to the Unified Parkinson’s Disease Rating Scale. Glial derived neurotrophic factor (GDNF) was also developed as a therapy that would modify PD [88]. However, the results of the clinical trial were not satisfactory, but the authors suggest hopes for longer GDNF treatments that it is possible to restore damaged cells in PD [88,89]. Trophic factors may represent a future PD treatment, however this approach has not met with great success [87].
Potential of Müller Glia for Retina Neuroprotection
Published in Current Eye Research, 2020
Karen Eastlake, Joshua Luis, G Astrid Limb
The glial cell line‐derived neurotrophic factor (GDNF) family of ligands include GDNF, neurturin (NTN), artemin (ARTN), and persephin (PSPN). Although not an archetype neurotrophin, GDNF signal in a manner similar to neurotrophins.61 They bind to the family of receptors ligands GFRα1 and GFRα2 and their complexes signal through the transmembrane RET receptor tyrosine kinase.62 In accordance with the neurotrophin family functions, GDNF has been shown to protect photoreceptors from damage in animal models of retinal degeneration.63 Müller glia not only release GDNF but also express GFRα1 and GFRα2 receptors. Exposure of these cells to high levels of glucose induces their release of GDNF, which protect them from apoptosis. On this basis, it has been suggested that GDNF may have a protective role in Müller cells survival during the early stages of diabetic retinopathy.64