scholarly journals Redundant roles of EGFR ligands in the ERK activation waves during collective cell migration

2021 ◽  
Vol 5 (1) ◽  
pp. e202101206
Author(s):  
Shuhao Lin ◽  
Daiki Hirayama ◽  
Gembu Maryu ◽  
Kimiya Matsuda ◽  
Naoya Hino ◽  
...  
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Transforming Growth Factor ◽  
Collective Cell Migration ◽  
Heparin Binding ◽  
Erk Activation ◽  
Egfr Ligands ◽  
Egfr Ligand ◽  
Epidermal Growth

Epidermal growth factor receptor (EGFR) plays a pivotal role in collective cell migration by mediating cell-to-cell propagation of extracellular signal-regulated kinase (ERK) activation. Here, we aimed to determine which EGFR ligands mediate the ERK activation waves. We found that epidermal growth factor (EGF)–deficient cells exhibited lower basal ERK activity than the cells deficient in heparin-binding EGF (HBEGF), transforming growth factor alpha (TGFα) or epiregulin (EREG), but all cell lines deficient in a single EGFR ligand retained the ERK activation waves. Surprisingly, ERK activation waves were markedly suppressed, albeit incompletely, only when all four EGFR ligands were knocked out. Re-expression of the EGFR ligands revealed that all but HBEGF could restore the ERK activation waves. Aiming at complete elimination of the ERK activation waves, we further attempted to knockout NRG1, a ligand for ErbB3 and ErbB4, and found that NRG1-deficiency induced growth arrest in the absence of all four EGFR ligand genes. Collectively, these results showed that EGFR ligands exhibit remarkable redundancy in the propagation of ERK activation waves during collective cell migration.

scholarly journals Redundant and specific roles of EGFR ligands in the ERK activation waves during collective cell migration of MDCK cells

2021 ◽  
Author(s):  
Shuhao Lin ◽  
Daiki Hirayama ◽  
Gembu Maryu ◽  
Kimiya Matsuda ◽  
Naoya Hino ◽  
...  
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Mdck Cells ◽  
Gene Knockout ◽  
Collective Cell Migration ◽  
Erk Activation ◽  
Egfr Ligands ◽  
Egfr Ligand ◽  
Epidermal Growth

Epidermal growth factor receptor (EGFR) plays a pivotal role in collective cell migration by mediating cell-to-cell propagation of extracellular signal-regulated kinase (ERK) activation. Here, we aimed to determine which EGFR ligands mediate the ERK activation waves by gene knockout. Four of the seven known EGFR ligands are expressed in MDCK cells. We found that epidermal growth factor (EGF)-deficient cells exhibited lower basal ERK activity than the cells deficient in heparin-binding EGF (HBEGF), transforming growth factor alpha (TGFα) or epiregulin (EREG), but all cell lines deficient in a single EGFR ligand retained the ERK activation waves. Therefore, we knocked out the EGFR ligand genes in decreasing order of expression. ERK activation waves were markedly suppressed, albeit incompletely, only when all four EGFR ligands were knocked-out. Re-expression of the EGFR ligands revealed that all but HBEGF could restore the ERK activation waves. Aiming at complete elimination of the ERK activation waves, we further attempted to knockout Nrg1, a ligand for ErbB3 and ErbB4, and found that Nrg1 deficiency induced growth arrest in the absence of all four EGFR ligand genes expressed in MDCK cells. Collectively, these results showed that EGFR ligands exhibit remarkable redundancy in the propagation of ERK activation waves during collective cell migration.

scholarly journals The Gene for Heparin-Binding Epidermal Growth Factor-Like Growth Factor is Stress-Inducible: Its Role in Cerebral Ischemia

1999 ◽  
Vol 19 (3) ◽  
pp. 307-320 ◽  
Author(s):  
Nobutaka Kawahara ◽  
Kazuhiko Mishima ◽  
Shigeki Higashiyama ◽  
Naoyuki Taniguchi ◽  
Akira Tamura ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Dentate Gyrus ◽  
Transforming Growth Factor ◽  
Adult Brain ◽  
Normal Brain ◽  
Heparin Binding ◽  
Epidermal Growth ◽  
Egf Family

The functions of the epidermal growth factor (EGF) family members in the adult brain are not known. This study investigated the changes in the expression of members of the EGF family following global ischemia employing in situ hybridization and immunohistochemical techniques to elucidate their roles in pathological conditions. EGF mRNA was not detected in either the control or the postischemic rat brain. Although transforming growth factor-α (TGF-α) mRNA was widely expressed in the normal brain, its expression did not change appreciably following ischemia. By contrast, heparin-binding EGF-like growth factor (HB-EGF) mRNA expression was rapidly increased in the CA3 sector and the dentate gyrus of the hippocampus, cortex, thalamus, and cerebellar granule and Purkinje cell layers. EGF receptor mRNA, which was widely expressed, also showed an increase in the CA3 sector and dentate gyrus. Conversely, HB-EGF mRNA did not show any increase prior to ischemic neuronal injury in the CA1 sector, the region most vulnerable to ischemia. Immunohistochemical detection of HB-EGF in the postischemic brain suggested a slight increase of immunostaining in the dentate gyrus of the hippocampus and the cortex. These findings showed that the gene encoding HB-EGF is stress-inducible, indicating the like-lihood that HB-EGF is a neuroprotective factor in cerebral ischemia.

scholarly journals Contemporary concepts of uterine fibroids’ pathogenesis

2019 ◽  
Vol 10 (1) ◽  
pp. 91-99
Author(s):  
Anna N. Taits ◽  
Nikolai N. Ruhljada ◽  
Valeriy I. Matukhin ◽  
Aleksandra D. Somova ◽  
Kristina A. Dudova
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Transforming Growth Factor ◽  
Uterine Fibroids ◽  
Transforming Growth Factor Β ◽  
Reproductive Age ◽  
Heparin Binding ◽  
Common Benign Tumor ◽  
Epidermal Growth

Uterine myoma is the most common benign tumor among women which affects mainly those of reproductive age. Moreover, the frequency of emergence of this pathology in population is growing while the age of patients is steadily decreasing. Despite the enormous prevalence of this disease, its pathogenesis has not been studied properly. This article is concerned with an analysis of publications devoted to the study of the mechanisms of growth and development of uterine fibroids, it provides some data on the role of various factors in its extension. The article concerns the most popular concepts of the pathogenesis of this disease according to which the illness may be caused by increased levels of sex hormones (estrogens and progestins), enhanced expression of their receptors, impaired apoptosis, the effect of growth factors (e. g. epidermal growth factor, heparin-binding epidermal growth factor, acid and basic fibroblast growth factors, vascular endothelial growth factor, insulin-like growth factor, platelet-derived growth factor, transforming growth factor-β, activin, myostatin), abnormal deposition extracellular matrix, genetic (chromosomal aberration and various MED12 gene defect) and epigenetic mechanisms (such as action microRNA), circulatory disorders and impairment of cell differentiation from a population of accessory stem cells. However, it is noted that the pathogenesis of this pathology requires further detailed study, as the understanding of the processes leading to its development could greatly contribute to the improvement of the tactics of treatment and possibly allow to elaborate some preventive measures to avert the development of fibroids.

scholarly journals Role of Epidermal Growth Factor Receptor (EGFR) and Its Ligands in Kidney Inflammation and Damage

2018 ◽  
Vol 2018 ◽  
pp. 1-22 ◽  
Author(s):  
Sandra Rayego-Mateos ◽  
Raul Rodrigues-Diez ◽  
Jose Luis Morgado-Pascual ◽  
Floris Valentijn ◽  
Jose M. Valdivielso ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Renal Disease ◽  
Transforming Growth Factor ◽  
Growth Factor Receptor ◽  
Therapeutic Strategies ◽  
Egfr Ligands ◽  
Pathway Activation ◽  
Epidermal Growth

Chronic kidney disease (CKD) is characterized by persistent inflammation and progressive fibrosis, ultimately leading to end-stage renal disease. Although many studies have investigated the factors involved in the progressive deterioration of renal function, current therapeutic strategies only delay disease progression, leaving an unmet need for effective therapeutic interventions that target the cause behind the inflammatory process and could slow down or reverse the development and progression of CKD. Epidermal growth factor receptor (EGFR) (ERBB1), a membrane tyrosine kinase receptor expressed in the kidney, is activated after renal damage, and preclinical studies have evidenced its potential as a therapeutic target in CKD therapy. To date, seven official EGFR ligands have been described, including epidermal growth factor (EGF) (canonical ligand), transforming growth factor-α, heparin-binding epidermal growth factor, amphiregulin, betacellulin, epiregulin, and epigen. Recently, the connective tissue growth factor (CTGF/CCN2) has been described as a novel EGFR ligand. The direct activation of EGFR by its ligands can exert different cellular responses, depending on the specific ligand, tissue, and pathological condition. Among all EGFR ligands, CTGF/CCN2 is of special relevance in CKD. This growth factor, by binding to EGFR and downstream signaling pathway activation, regulates renal inflammation, cell growth, and fibrosis. EGFR can also be “transactivated” by extracellular stimuli, including several key factors involved in renal disease, such as angiotensin II, transforming growth factor beta (TGFB), and other cytokines, including members of the tumor necrosis factor superfamily, showing another important mechanism involved in renal pathology. The aim of this review is to summarize the contribution of EGFR pathway activation in experimental kidney damage, with special attention to the regulation of the inflammatory response and the role of some EGFR ligands in this process. Better insights in EGFR signaling in renal disease could improve our current knowledge of renal pathology contributing to therapeutic strategies for CKD development and progression.

scholarly journals Substrate Selectivity of Epidermal Growth Factor-Receptor Ligand Sheddases and their Regulation by Phorbol Esters and Calcium Influx

2007 ◽  
Vol 18 (1) ◽  
pp. 176-188 ◽  
Author(s):  
Keisuke Horiuchi ◽  
Sylvain Le Gall ◽  
Marc Schulte ◽  
Takafumi Yamaguchi ◽  
Karina Reiss ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Phorbol Esters ◽  
Calcium Influx ◽  
Growth Factor Receptor ◽  
Egfr Ligands ◽  
Egfr Ligand ◽  
Epidermal Growth ◽  
Ligand Shedding

Signaling via the epidermal growth factor receptor (EGFR), which has critical roles in development and diseases such as cancer, is regulated by proteolytic shedding of its membrane-tethered ligands. Sheddases for EGFR-ligands are therefore key signaling switches in the EGFR pathway. Here, we determined which ADAMs (a disintegrin and metalloprotease) can shed various EGFR-ligands, and we analyzed the regulation of EGFR-ligand shedding by two commonly used stimuli, phorbol esters and calcium influx. Phorbol esters predominantly activate ADAM17, thereby triggering a burst of shedding of EGFR-ligands from a late secretory pathway compartment. Calcium influx stimulates ADAM10, requiring its cytoplasmic domain. However, calcium influx-stimulated shedding of transforming growth factor α and amphiregulin does not require ADAM17, even though ADAM17 is essential for phorbol ester-stimulated shedding of these EGFR-ligands. This study provides new insight into the machinery responsible for EGFR-ligand release and thus EGFR signaling and demonstrates that dysregulated EGFR-ligand shedding may be caused by increased expression of constitutively active sheddases or activation of different sheddases by distinct stimuli.

Induction of Collecting Duct MorphogenesisIn Vitroby Heparin-Binding Epidermal Growth Factor-Like Growth Factor

2001 ◽  
Vol 12 (5) ◽  
pp. 964-972
Author(s):  
TSUKASA TAKEMURA ◽  
SATOSHI HINO ◽  
HIROAKI KUWAJIMA ◽  
HIDEHIKO YANAGIDA ◽  
MITSURU OKADA ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Transforming Growth Factor ◽  
Collecting Duct ◽  
Transforming Growth Factor Β ◽  
Heparin Binding ◽  
Collagen Gels ◽  
Ureteric Bud ◽  
Kinase C ◽  
Epidermal Growth

Abstract. Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the epidermal growth factor family of growth factors, is synthesized as a membrane-an-chored precursor (proHB-EGF) that is capable of stimulating adjacent cells in a juxtacrine manner. ProHB-EGF is cleaved in a protein kinase C-dependent process, to yield the soluble form. It was observed that HB-EGF acts as a morphogen for the collecting duct system in developing kidneys. HB-EGF protein was expressed in the ureteric bud of embryonic kidneys. Cultured mouse ureteric bud cells (UBC) produced HB-EGF via protein kinase C activation. After stimulation with phorbol ester (12-O-tetradecanoylphorbol-13-acetate) or recombinant soluble HB-EGF, UBC cultured in three-dimensional collagen gels formed short tubules with varied abundant branches. When proHB-EGF-transfected UBC were stimulated with 12-O-tetradecanoylphorbol-13-acetate and cultured in collagen gels, they exhibited linear growth, forming long tubular structures with few branches at the time of appearance of proHB-EGF on the cell surface. The structures exhibited a strong resemblance to the early branching ureteric bud of embryonic kidneys. When UBC were cultured in the presence of transforming growth factor-β and soluble HB-EGF, they formed long tubules and few branches, similar to the structures observed in proHB-EGF-transfected UBC. These cells exhibited apical-basolateral polarization and expression of the water channel aquaporin-2. These findings indicate that soluble HB-EGF and proHB-EGF induce branching tubulogenesis in UBC in different ways. Juxtacrine activation by proHB-EGF or the synergic action of soluble HB-EGF with transforming growth factor-β is important for well balanced morphogenesis of the collecting duct system.

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.

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