scholarly journals FRMD8 promotes inflammatory and growth factor signalling by stabilising the iRhom/ADAM17 sheddase complex

2018 ◽  
Author(s):  
Ulrike Künzel ◽  
Adam G. Grieve ◽  
Yao Meng ◽  
Sally A. Cowley ◽  
Matthew Freeman
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Inflammatory Cytokine ◽  
Egf Receptor ◽  
Receptor Ligands ◽  
Ferm Domain ◽  
Human Macrophages ◽  
Mouse Tissues ◽  
N Terminus ◽  
Growth Factor Signalling

AbstractMany intercellular signals are synthesised as transmembrane precursors that are released by proteolytic cleavage (‘shedding’) from the cell surface. ADAM17, a membrane-tethered metalloprotease, is the primary shedding enzyme responsible for the release of the inflammatory cytokine TNFα and several EGF receptor ligands. ADAM17 exists in complex with the rhomboid-like iRhom proteins, which act as cofactors that regulate ADAM17 substrate shedding. Here we report that the poorly characterised FERM domain-containing protein FRMD8 is a new component of iRhom2/ADAM17 sheddase complex. FRMD8 binds to the cytoplasmic N-terminus of iRhoms, and is necessary to stabilise the iRhoms and ADAM17 beyond the Golgi. In the absence of FRMD8, iRhom2 and ADAM17 are degraded via the endolysosomal pathway, resulting in the reduction of ADAM17-mediated shedding. We have confirmed the pathophysiological significance of FRMD8 in iPSC-derived human macrophages and mouse tissues, thus demonstrating its role in the regulated release of multiple cytokine and growth factor signals.

scholarly journals FRMD8 promotes inflammatory and growth factor signalling by stabilising the iRhom/ADAM17 sheddase complex

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Ulrike Künzel ◽  
Adam Graham Grieve ◽  
Yao Meng ◽  
Boris Sieber ◽  
Sally A Cowley ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Inflammatory Cytokine ◽  
Egf Receptor ◽  
Receptor Ligands ◽  
Ferm Domain ◽  
Human Macrophages ◽  
Mouse Tissues ◽  
N Terminus ◽  
Growth Factor Signalling

Many intercellular signals are synthesised as transmembrane precursors that are released by proteolytic cleavage (‘shedding’) from the cell surface. ADAM17, a membrane-tethered metalloprotease, is the primary shedding enzyme responsible for the release of the inflammatory cytokine TNFα and several EGF receptor ligands. ADAM17 exists in complex with the rhomboid-like iRhom proteins, which act as cofactors that regulate ADAM17 substrate shedding. Here we report that the poorly characterised FERM domain-containing protein FRMD8 is a new component of the iRhom2/ADAM17 sheddase complex. FRMD8 binds to the cytoplasmic N-terminus of iRhoms and is necessary to stabilise iRhoms and ADAM17 at the cell surface. In the absence of FRMD8, iRhom2 and ADAM17 are degraded via the endolysosomal pathway, resulting in the reduction of ADAM17-mediated shedding. We have confirmed the pathophysiological significance of FRMD8 in iPSC-derived human macrophages and mouse tissues, thus demonstrating its role in the regulated release of multiple cytokine and growth factor signals.

Met -/- kidneys express epithelial cells that chemotax and form tubules in response to EGF receptor ligands

1997 ◽  
Vol 272 (2) ◽  
pp. F222-F228
Author(s):  
C. Kjelsberg ◽  
H. Sakurai ◽  
K. Spokes ◽  
C. Birchmeier ◽  
I. Drummond ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cell ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Growth Factor Receptor ◽  
Receptor Ligands ◽  
Tubule Formation ◽  
Human Papillomavirus 16 ◽  
Immortalized Cells

The growth factor/receptor combination of hepatocyte growth factor (HGF)/c-met has been postulated to be critical for mesenchymal-to-epithelial conversion and tubule formation in the developing kidney. We therefore isolated and immortalized cells from embryonic kidneys of met -/- transgenic mice to determine whether these cells were epithelial and able to chemotax and form tubules in vitro. The cells were immortalized with retrovirus expressing human papillomavirus 16 (HPV 16) E6/E7 genes. Two rapidly dividing clones were isolated and found to express the epithelial cell markers cytokeratin, zonula occludens-1, and E-cadherin but not to express the fibroblast marker vimentin. The met -/- cells were able to chemotax in response to epidermal growth factor and transforming growth factor-alpha (TGF-alpha) and form tubules in vitro in response to TGF-alpha but not HGF. These experiments suggest that the HGF/c-met axis is not essential for epithelial cell development in the embryonic kidney and demonstrate that other growth factors are capable of supporting early tubulogenesis.

Cell-Surface Galactosyltransferase Acts as a Modulator of Rat and Human Acinar Cell Proliferation

1990 ◽  
Vol 4 (1) ◽  
pp. 45-60 ◽  
Author(s):  
M.G. Humphreys-Beher ◽  
T. Zelles ◽  
N. Maeda ◽  
K.R. Purushotham ◽  
N. Cassisi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Cell Surface ◽  
Parotid Gland ◽  
Adenoid Cystic Carcinoma ◽  
Acinar Cell ◽  
Egf Receptor ◽  
Neoplastic Tissue ◽  
Direct Role ◽  
Adenoid Cystic

Several physiological parameters were examined for inducing acinar cell proliferation and corresponding increased expression of β1-4 galactosyltransferase. In this study, dietary changes causing acinar cell proliferation included the following: the introduction of animals to a liquid diet (causing gland atrophy) followed by re-introduction of solid chow, gustatory stimulation provided by the introduction of 0.5% citric acid to animal drinking water, and removal of the submandibular gland with subsequent reliance on the parotid gland for saliva protein and fluid. Alterations in growth factor levels were produced by injecting animals with a chronic (three-day) regimen of either nerve growth factor (NGF) or epidermal growth factor (EGF). In all cases of acinar cell proliferation in vivo, generated by the above treatments, cell-surface galactosyltransferase was detected along with the unique expression of a 4.5-kb proliferation-associated mRNA. Parotid gland proliferation could be blocked in all cases by the injection of the galactosyltransferase specific modifier protein, a-lactalbumin. Propranolol, a β-adrenergic receptor antagonist, blocked proliferation in all cases except EGF treatment. EGFinduced proliferation could, however, be prevented if the animals were treated with monoclonal antibody to EGF receptor or with the galactosyltransferase modifier a-lactalbumin. As a comparison, human parotid tissue samples obtained from neoplastic pleomorphic adenomas, mucoepidermoid carcinoma, adenoid cystic carcinoma, and a bulimia patient were analyzed for galactosyltransferase expression by Northern blot of mRNA and plasma membrane isolation. Elevated levels of galactosyltransferase were found in all neoplastic tissue preparations as well as in the bulimia sample. Amylase synthesis was reduced in samples compared with surrounding normal tissue from the same patient. In vitro cell culturing of pleomorphic adenoma cells in the presence of galactosyltransferase modifier a-lactalbumin and substrate UDP-galactose inhibited proliferation in a dose-dependent fashion. Southern blot analysis of DNA from neoplastic parotid cells showed an alteration in chromosomal gene structure for the galactosyltransferase activator cDNA from the adenoid cystic carcinoma. These results for induced acinar cell proliferation as well as human neoplastic pathologies suggest a direct role for cell surface β1-4 galactosyltransferase in signaling growth. Furthermore, the proliferation-associated activity of galactosyltransferase suggests that it may be considered as a new type of cell growth regulator.

scholarly journals Endosomal receptor kinetics determine the stability of intracellular growth factor signalling complexes

2007 ◽  
Vol 402 (3) ◽  
pp. 537-549 ◽  
Author(s):  
A. Rami Tzafriri ◽  
Elazer R. Edelman
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Dissociation Constant ◽  
Specific Binding ◽  
Ph Dependence ◽  
Growth Factor Receptor ◽  
Factor Binding ◽  
Receptor Complexes ◽  
Growth Factor Signalling ◽  
The Stability

There is an emerging paradigm that growth factor signalling continues in the endosome and that cell response to a growth factor is defined by the integration of cell surface and endosomal events. As activated receptors in the endosome are exposed to a different set of binding partners, they probably elicit differential signals compared with when they are at the cell surface. As such, complete appreciation of growth factor signalling requires understanding of growth factor–receptor binding and trafficking kinetics both at the cell surface and in endosomes. Growth factor binding to surface receptors is well characterized, and endosomal binding is assumed to follow surface kinetics if one accounts for changes in pH. Yet, specific binding kinetics within the endosome has not been examined in detail. To parse the factors governing the binding state of endosomal receptors we analysed a whole-cell mathematical model of epidermal growth factor receptor trafficking and binding. We discovered that the stability of growth factor–receptor complexes within endosomes is governed by three primary independent factors: the endosomal dissociation constant, total endosomal volume and the number of endosomal receptors. These factors were combined into a single dimensionless parameter that determines the endosomal binding state of the growth factor–receptor complex and can distinguish different growth factors from each other and different cell states. Our findings indicate that growth factor binding within endosomal compartments cannot be appreciated solely on the basis of the pH-dependence of the dissociation constant and that the concentration of receptors in the endosomal compartment must also be considered.

scholarly journals Localization dynamics of endogenous fluorescently labeled RAF1 in EGF-stimulated cells

2019 ◽  
Vol 30 (4) ◽  
pp. 506-523
Author(s):  
Sachin V. Surve ◽  
Paul J. Myers ◽  
Samantha A. Clayton ◽  
Simon C. Watkins ◽  
Matthew J. Lazzara ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Surface ◽  
Gene Editing ◽  
Egf Receptor ◽  
Subcellular Fractionation ◽  
Receptor Endocytosis ◽  
Downstream Effectors ◽  
Epidermal Growth

Activation of the epidermal growth factor (EGF) receptor (EGFR) at the cell surface initiates signaling through the RAS-RAF-MAPK/ERK1/2 pathway and receptor endocytosis. Whether this signaling continues from endosomes remains unclear, because RAS is predominantly located on the plasma membrane, and the localization of endogenous RAF kinases, downstream effectors of RAS, is not defined. To examine RAF localization, we labeled endogenous RAF1 with mVenus using gene editing. From 10 to 15% of RAF1-mVenus (<2000 molecules/cell), which was initially entirely cytosolic, transiently translocated to the plasma membrane after EGF stimulation. Following an early burst of translocation, the membrane-associated RAF1-mVenus was undetectable by microscopy or subcellular fractionation, and this pool was estimated to be <200 molecules per cell. In contrast, persistent EGF-dependent translocation of RAF1-mVenus to the plasma membrane was driven by the RAF inhibitor sorafenib, which increases the affinity of Ras-GTP:RAF1 interactions. RAF1-mVenus was not found in EGFR-containing endosomes under any conditions. Computational modeling of RAF1 dynamics revealed that RAF1 membrane abundance is controlled most prominently by association and dissociation rates from RAS-GTP and by RAS-GTP concentration. The model further suggested that the relatively protracted activation of the RAF-MEK1/2-ERK1/2 module, in comparison with RAF1 membrane localization, may involve multiple rounds of cytosolic RAF1 rebinding to active RAS at the membrane.

scholarly journals EGF receptor ligands: recent advances

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2270 ◽  
Author(s):  
Bhuminder Singh ◽  
Graham Carpenter ◽  
Robert J. Coffey
Keyword(s):  
Growth Factor ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Heparin Binding ◽  
Receptor Ligands ◽  
Affinity Ligands ◽  
Egfr Ligands ◽  
Ligand Interactions ◽  
Epidermal Growth ◽  
The Individual

Seven ligands bind to and activate the mammalian epidermal growth factor (EGF) receptor (EGFR/ERBB1/HER1): EGF, transforming growth factor-alpha (TGFA), heparin-binding EGF-like growth factor (HBEGF), betacellulin (BTC), amphiregulin (AREG), epiregulin (EREG), and epigen (EPGN). Of these, EGF, TGFA, HBEGF, and BTC are thought to be high-affinity ligands, whereas AREG, EREG, and EPGN constitute low-affinity ligands. This focused review is meant to highlight recent studies related to actions of the individual EGFR ligands, the interesting biology that has been uncovered, and relevant advances related to ligand interactions with the EGFR.

Sign in / Sign up

Export Citation Format

Share Document