Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Surinder K. Batra, Moorthy P. Ponnusamy in Gene Regulation and Therapeutics for Cancer, 2021
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].
Handbook of Phytochemical Constituents of GRAS Herbs and Other Economic Plants
James A. Duke in Handbook of Phytochemical Constituents of GRAS Herbs and Other Economic Plants, 2017
“Sea Wormwood”ARTEMIN PL JSGARTEMISIN BDCCODAVANONE PL JSGFAT 220,000 SD CRCHYDROXYDAVANONE PL JSG1BETA-HYDROXY-6BET A,7 ALPHA, 11BETAH-SELEN-4-EN-6,12-OLIDE PL JSGMARITIMIN PL JSGPROTEIN 438,000 SD CRCSANTONIN 2,000 PL HHBL-ALPHA-SANTONIN BDCCO
Characteristics, Events, and Stages in Tumorigenesis
Franklyn De Silva, Jane Alcorn in The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Interleukin 1 (IL1), IL12, retinoic acid, metalloproteinase inhibitors, endostatin, angiostatin, and interferons are examples for naturally occurring angiogenesis inhibitors [1076]. Various factors like VEGF, platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), basic fibroblast growth factor (FGF), hypoxia inducible factor 1 (HIF1), monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein 1β (MIP1β), IL8, IL6, regulated on activation-normal T-cell expressed and secreted (RANTES), angiogenin, tumor necrosis factor alpha (TNFα), granulocyte colony-stimulating factor (G-CSF), placental growth factor (PGF), epidermal growth factor (EGF), transforming growth factor alpha (TGFα), TGFβ, amphiregulin, artemin, coagulation factor III, among others have been identified to be proangiogenic in many solid tumors [1076, 1077, 1087–1090]. This abundance of angiogenic factors and the redundancies that exist in the angiogenic process likely explain the suboptimal effectiveness or resistance of cancer to treatment with single antiangiogenic agents [1076].
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
An updated patent review of rearranged during transfection (RET) kinase inhibitors (2016–present)
Published in Expert Opinion on Therapeutic Patents, 2022
Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase encoded by the RET proto-oncogene located on chromosome 10. RET is integral for the development of kidneys and the enteric nervous system during embryogenesis.1 RET is expressed in neural cells and is required for proliferation, differentiation, and survival of these cells[1]. In addition, RET signaling is known to contribute to the regulation and function of hematopoietic cells and spermatogenesis [2,3]. The structure of RET (Figure 1) is similar to other receptor tyrosine kinases, and consists of an intracellular tyrosine kinase domain, a transmembrane domain, and an extracellular domain with four cadherin-like domains and a conserved cysteine region (C609, C611, C618, C620, C630, and C640)[4]. This cysteine region plays a key role in protein conformation and ligand binding [5,6]. RET activating ligands belong to the glial-cell derived neurotrophic factor (GDNF) family of ligands (GFLs) and include GDNF, neurturin, artemin, and persephin[7]. Ligands binds to the GDNF family receptor-α (GFR-α), which then causes dimerization of RET (Figure 1) and subsequent activation through autophosphorylation of the intracellular tyrosine kinase domain (Y687, Y752, Y806, Y809, Y826, Y900, Y905, Y928, Y981, Y1015, Y1062, and Y1062). Following autophosphorylation, multiple signaling pathways (such as PI3K, MAPK, JAK/STAT, and PKC pathways) are activated that regulate survival, differentiation, and proliferation[7].
Delivery of neurotrophic factors in the treatment of age-related chronic neurodegenerative diseases
Published in Expert Opinion on Drug Delivery, 2020
Smrithi Padmakumar, Maie S. Taha, Ekta Kadakia, Benjamin S. Bleier, Mansoor M. Amiji
This family consists of homodimeric polypeptides: GDNF, neurturin (NRTN), artemin (ARTN), and persephin (PSPN), which also belong to the transforming growth factor β superfamily. GDNF is the first identified member in this family with an important role in survival of midbrain dopaminergic neurons in a specific manner [25]. Other GFLs have shown similar potent protective effects for dopaminergic neurons [26]. GDNF is also considered as one of the most protective factors for motor neurons and has showed a significantly higher benefit than neurotrophins in regenerating sensory axons in a spinal cord injury rat model [27]. GFLs exert their neuroprotective functions both centrally and peripherally, except for PSPN which functions only centrally. GFLs also have roles in synaptic transmission and activity-dependent neuroplasticity. They function by activating RET tyrosine kinase via binding to the GDNF family receptor-α (GFRα) that is anchored to the plasma membrane by glycosyl phosphatidylinositol, which eventually leads to activation of PLCγ, PI3K, and mitogen-activated protein kinase (MAPK) pathways [23]. GDNF binding to neural cell adhesion molecule was also shown to induce signaling for mediating neurite outgrowth [28].
Related Knowledge Centers
- Nerve Growth Factor
- Neurotrophic Factors
- Protein
- Transforming Growth Factor Beta
- Sympathetic Nervous System
- Mitosis
- Gene
- Gdnf Family of Ligands
- Ret Proto-Oncogene
- Dopaminergic Cell Groups