scholarly journals Reduced EGFR signaling in progenitor cells of the adult subventricular zone attenuates oligodendrogenesis after demyelination

2007 ◽  
Vol 3 (3) ◽  
pp. 209-220 ◽  
Author(s):  
Adan Aguirre ◽  
Vittorio Gallo
Keyword(s):  
Growth Factor ◽  
Progenitor Cells ◽  
Subventricular Zone ◽  
Transforming Growth Factor ◽  
Mammalian Brain ◽  
Heparin Binding ◽  
Egfr Signaling ◽  
Transforming Growth Factor Α ◽  
Physiological Conditions ◽  
Focal Demyelination

AbstractNeural progenitor cells that express the NG2 proteoglycan are present in different regions of the adult mammalian brain where they display distinct morphologies and proliferative rates. In the developing postnatal and adult mouse, NG2+ cells represent a major cell population of the subventricular zone (SVZ). NG2+ cells divide in the anterior and lateral region of the SVZ, and are stimulated to proliferate and migrate out of the SVZ by focal demyelination of the corpus callosum (CC). Many NG2+ cells are labeled by GFP-retrovirus injection into the adult SVZ, demonstrating that NG2+ cells actively proliferate under physiological conditions and after demyelination. Under normal physiological conditions and after focal demyelination, proliferation of NG2+ cells is significantly attenuated in wa2 mice, which are characterized by reduced signaling of the epidermal growth factor receptor (EGFR). This results in reduced SVZ-to-lesion migration of NG2+ cells and oligodendrogenesis in the lesion. Expression of vascular endothelial growth factor (VEGF) and EGFR ligands, such as heparin binding-EGF and transforming growth factor α, is upregulated in the SVZ after focal demyelination of the CC. EGF-induced oligodendrogenesis and myelin protein expression in wild-type SVZ cells in culture are significantly attenuated in wa2 SVZ cells. Our results demonstrate that the response of NG2+ cells in the SVZ and their subsequent differentiation in CC after focal demyelination depend on EGFR signaling.

scholarly journals Transforming growth factor-α in the mammalian brain

1989 ◽  
Vol 264 (7) ◽  
pp. 3880-3883
Author(s):  
J E Kudlow ◽  
A W Leung ◽  
M S Kobrin ◽  
A J Paterson ◽  
S L Asa
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mammalian Brain ◽  
Transforming Growth Factor Α ◽  
Factor Α

scholarly journals Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands

2004 ◽  
Vol 164 (5) ◽  
pp. 769-779 ◽  
Author(s):  
Umut Sahin ◽  
Gisela Weskamp ◽  
Kristine Kelly ◽  
Hong-Ming Zhou ◽  
Shigeki Higashiyama ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Growth Factor Receptor ◽  
Experimental System ◽  
Heparin Binding ◽  
Embryonic Cells ◽  
Transforming Growth Factor Α ◽  
Egfr Ligands ◽  
Egfr Ligand

All ligands of the epidermal growth factor receptor (EGFR), which has important roles in development and disease, are released from the membrane by proteases. In several instances, ectodomain release is critical for activation of EGFR ligands, highlighting the importance of identifying EGFR ligand sheddases. Here, we uncovered the sheddases for six EGFR ligands using mouse embryonic cells lacking candidate-releasing enzymes (a disintegrin and metalloprotease [ADAM] 9, 10, 12, 15, 17, and 19). ADAM10 emerged as the main sheddase of EGF and betacellulin, and ADAM17 as the major convertase of epiregulin, transforming growth factor α, amphiregulin, and heparin-binding EGF-like growth factor in these cells. Analysis of adam9/12/15/17−/− knockout mice corroborated the essential role of adam17−/− in activating the EGFR in vivo. This comprehensive evaluation of EGFR ligand shedding in a defined experimental system demonstrates that ADAMs have critical roles in releasing all EGFR ligands tested here. Identification of EGFR ligand sheddases is a crucial step toward understanding the mechanism underlying ectodomain release, and has implications for designing novel inhibitors of EGFR-dependent tumors.

scholarly journals Targeting cartilage EGFR pathway for osteoarthritis treatment

2021 ◽  
Vol 13 (576) ◽  
pp. eabb3946
Author(s):  
Yulong Wei ◽  
Lijun Luo ◽  
Tao Gui ◽  
Feifan Yu ◽  
Lesan Yan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Protective Action ◽  
Growth Factor Receptor ◽  
Cartilage Degeneration ◽  
Joint Disease ◽  
Heparin Binding ◽  
Transforming Growth Factor Α ◽  
Knee Oa ◽  
Egfr Ligand

Osteoarthritis (OA) is a widespread joint disease for which there are no disease-modifying treatments. Previously, we found that mice with cartilage-specific epidermal growth factor receptor (EGFR) deficiency developed accelerated knee OA. To test whether the EGFR pathway can be targeted as a potential OA therapy, we constructed two cartilage-specific EGFR overactivation models in mice by overexpressing heparin binding EGF-like growth factor (HBEGF), an EGFR ligand. Compared to wild type, Col2-Cre HBEGF-overexpressing mice had persistently enlarged articular cartilage from adolescence, due to an expanded pool of chondroprogenitors with elevated proliferation ability, survival rate, and lubricant production. Adult Col2-Cre HBEGF-overexpressing mice and Aggrecan-CreER HBEGF-overexpressing mice were resistant to cartilage degeneration and other signs of OA after surgical destabilization of the medial meniscus (DMM). Treating mice with gefitinib, an EGFR inhibitor, abolished the protective action against OA in HBEGF-overexpressing mice. Polymeric micellar nanoparticles (NPs) conjugated with transforming growth factor–α (TGFα), a potent EGFR ligand, were stable and nontoxic and had long joint retention, high cartilage uptake, and penetration capabilities. Intra-articular delivery of TGFα-NPs effectively attenuated surgery-induced OA cartilage degeneration, subchondral bone plate sclerosis, and joint pain. Genetic or pharmacologic activation of EGFR revealed no obvious side effects in knee joints and major vital organs in mice. Together, our studies demonstrate the feasibility of using nanotechnology to target EGFR signaling for OA treatment.

scholarly journals Apple polyphenol extracts prevent aspirin-induced damage to the rat gastric mucosa

2008 ◽  
Vol 100 (6) ◽  
pp. 1228-1236 ◽  
Author(s):  
Giuseppe D'Argenio ◽  
Giovanna Mazzone ◽  
Concetta Tuccillo ◽  
Ilenia Grandone ◽  
Antonietta G. Gravina ◽  
...  
Keyword(s):  
Growth Factor ◽  
Gastric Mucosa ◽  
Protein Expression ◽  
Transforming Growth Factor ◽  
Gastric Injury ◽  
Heparin Binding ◽  
Transforming Growth Factor Α ◽  
Rat Gastric Mucosa ◽  
Mrna And Protein Expression ◽  
Cox 2

Aspirin causes gastroduodenal ulcers and complications. Food bioactive compounds could exert beneficial effects in the gastrointestinal tract. We evaluated whether apple polyphenol extract (APE) reduced aspirin-induced injury to the rat gastric mucosa. Rats were treated with APE (10− 4 m catechin equivalent) before oral aspirin (200 mg/kg). Cyclo-oxygenase-2 (COX-2), transforming growth factor-α (TGFα) and heparin-binding epidermal-growth-factor-like growth factor (HB-EGF) mRNA and protein expression were assessed by RT-PCR and Western blot analysis, respectively; malondialdehyde (MDA) was determined by HPLC; gastric secretion was evaluated in pylorus-ligated rats. APE decreased acute and chronic aspirin injury both macroscopically and microscopically (approximately 50 % decrease in lesion score; P < 0·05). Aspirin up-regulated mRNA and protein expression of COX-2 and HB-EGF, but not of TGFα; APE reduced aspirin-induced mRNA and protein over-expression of COX-2 and HB-EGF; aspirin significantly increased gastric MDA and this effect was counteracted by APE pre-treatment. APE did not significantly affect gastric acid secretion. In conclusion, APE reduces aspirin-induced gastric injury independently of acid inhibition. We speculate that APE might be of therapeutic use in the prophylaxis of aspirin-related gastropathy.

scholarly journals NeissLock provides an inducible protein anhydride for covalent targeting of endogenous proteins

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Arne H. A. Scheu ◽  
Sheryl Y. T. Lim ◽  
Felix J. Metzner ◽  
Shabaz Mohammed ◽  
Mark Howarth
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Growth Factor Receptor ◽  
Molecular Engineering ◽  
Nucleophilic Attack ◽  
High Yield ◽  
Protein Chemistry ◽  
Transforming Growth Factor Α ◽  
Endogenous Proteins

AbstractThe Neisseria meningitidis protein FrpC contains a self-processing module (SPM) undergoing autoproteolysis via an aspartic anhydride. Herein, we establish NeissLock, using a binding protein genetically fused to SPM. Upon calcium triggering of SPM, the anhydride at the C-terminus of the binding protein allows nucleophilic attack by its target protein, ligating the complex. We establish a computational tool to search the Protein Data Bank, assessing proximity of amines to C-termini. We optimize NeissLock using the Ornithine Decarboxylase/Antizyme complex. Various sites on the target (α-amine or ε-amines) react with the anhydride, but reaction is blocked if the partner does not dock. Ligation is efficient at pH 7.0, with half-time less than 2 min. We arm Transforming Growth Factor-α with SPM, enabling specific covalent coupling to Epidermal Growth Factor Receptor at the cell-surface. NeissLock harnesses distinctive protein chemistry for high-yield covalent targeting of endogenous proteins, advancing the possibilities for molecular engineering.

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