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Transforming Growth Factor-α and Epidermal Growth Factor
Published in Jason Kelley, Cytokines of the Lung, 2022
The cDNA for human HB-EGF predicts a 208-amino acid translation product that contains two hydrophobic regions, similar to those described for EGF and TGF-α (Higashiyama et al., 1991). The first 19 amino acids of the nascent polypeptide backbone are hydrophobic residues representing a putative signal sequence. The second hydrophobic region, composed of amino acids 161–184, forms a presumptive stop transfer sequence that spans the plasma membrane. This presumed transmembrane region separates the protein into an intracellular domain of 141 amino acids and a cytoplasmic domain of 24 residues. The secreted form of HB-EGF is likely to be generated by proteolytic cleavage within the extracellular domain, in a manner similar to that of EGF and TGF-α, however, studies detailing HB-EGF precursor-product relationships have not been reported.
Use of Molecular Markers of Endometrial Receptivity
Published in Botros Rizk, Yakoub Khalaf, Controversies in Assisted Reproduction, 2020
Alejandro Rincón, David Bolumar, Diana Valbuena, Carlos Simón
Meanwhile, studies of different growth factors have highlighted the heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF). HB-EGF is a glycoprotein from the EGF family secreted by macrophages and monocytes, which play a crucial role in epidermal injury healing, epithelialization, cell proliferation modulation, and decidualization. HB-EGF appears in the luminal epithelial layer, and its expression is modulated during the menstrual cycle, progressing from basal expression during the proliferative stage to maximum expression during the mid-secretory phase (31). Considering its ease of determination together with its modulation during the cycle and possible functions related to adhesion and implantation, HB-EGF is considered an endometrial biomarker candidate.
Embryo/fetal–maternal cross talk
Published in Carlos Simón, Linda C. Giudice, The Endometrial Factor, 2017
Nuria Balaguer, Francisco Dominguez, Carlos Simón, Felipe Vilella
Growth factors comprise a group of peptides and polypeptides that are usually divided into families based primarily on their structural characteristics (40). They interact with specific cell membrane receptors, thus initiating intracellular signaling pathways (41). The major families include epidermal growth factors (EGFs), TGFβ, fibroblast growth factors (FGFs), insulin-like growth factors, and platelet-derived growth factors (PDGFs). The EGF family encompasses EGF itself, TGFα, HB-EGF, amphiregulin, β-cellulin (BTC), epiregulin (ER), and neuregulins (38). Specifically, they interact with the receptor subtypes of the ErbB family, which comprises four receptor tyrosine kinases: ErbB1 (EGF-R), ErbB2, ErbB3, and ErbB4 (42). Spatiotemporal expression patterns of EGF gene family members and ErbB in the uterus during the peri-implantation period suggest compartmentalized functions of EGF-like growth factors in implantation (43–47). HB-EGF appears to play a critical role in this process, as well as in embryo development, since its expression reaches its highest level during the late secretory phase, a period of maximum receptivity (48). Moreover, decreasing levels lead to pregnancy complications, such as preeclampsia and small for gestational age (SGA), due to aberrant trophoblast invasion, and also to IUGR due to increased apoptosis (49). Concurrently, cells expressing the transmembrane form of HB-EGF adhere to human blastocysts displaying cell surface ErbB4 (50). In support of this molecular event, Paria et al. (51) demonstrated that ErbB4 was expressed by day 4 blastocysts at both the protein and mRNA levels. This was located primarily at the submyometrial stroma and connective tissues with basal levels of expression throughout the stroma (52). Besides HB-EGF, the luminal epithelium also expresses BTC and ER as ligands at the site of implantation that can interact with ErbB1 and ErbB4. Thus, the contribution of these various ligands to implantation may be redundant. In general, the expression of multiple ligands and multiple ErbB family receptors might be a protective mechanism to ensure a high probability of blastocyst development and implantation.
Novel therapeutic perspectives for crescentic glomerulonephritis through targeting parietal epithelial cell activation and proliferation
Published in Expert Opinion on Therapeutic Targets, 2023
Yanjie Huang, Xueru Zhao, Qiushuang Zhang, Xiaoqing Yang, Gailing Hou, Chaoqun Peng, Mengzhen Jia, Li Zhou, Tatsuo Yamamoto, Jian Zheng
HB-EGF induces cell proliferation and migration [69,70]. Under physiological conditions, it is expressed only at low levels in PECs and podocytes [71]. EGFR is a member of the epidermal growth factor receptor family of receptor tyrosine kinases [70], which is expressed in PECs and podocytes. They are inactive under physiological conditions. In the CrGN mouse model, the expression of HB-EGF in podocytes and PECs was substantially upregulated and induced the continuous phosphorylation of EGFR [69]. In the NTN mouse model, pro-HB-EGF was highly expressed in PECs, which was cleaved under the action of metalloproteinase to release soluble fragments, and soluble HB-EGF activated EGFR [69,70]. Disaggregated metalloproteinase (ADAM) and matrix metalloproteinase-3 can cleave proHB-EGF expressed by PECs. Soluble HB-EGF binds to the phosphorylated EGFR dimer on PECs or podocytes, and then activates Janus Kinase (JAK) in the intracellular segment. JAK can cause phosphorylation of the signal transducer and activator of transcription 3 (STAT3), which enters the nucleus to induce cell proliferation (Figure 2) [69,71]. Therefore, the HB-EGF/EGFR/JAK/STAT3 pathway participates in the formation of cellular crescents [72] and plays a key role in opening up new therapeutic prospects [73].
Pregnancy immune tolerance at the maternal-fetal interface
Published in International Reviews of Immunology, 2020
Xiaopeng Li, Jiayi Zhou, Min Fang, Bolan Yu
Innate lymphoid cells (ILCs) are divided into five major groups based on their cytokine production patterns and developmental transcription factor requirements: NK cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue-inducer (LTi) cells.61 Fetal LTi cells and postnatal ILC3s depend on the transcription factor RORγt. ILC3s are abundant in mucosal tissues where they contribute to defenses against pathogens and tissue homeostasis.62 Moreover, ILC3s with dominantly NCR positive phenotype are also identified in human decidua during early pregnancy, suggesting NCR+ILC3s may play a role in maintenance of pregnancy.63 ILC3s mainly produce CXCL8, which plays a role in decidual tissue building/remodeling.12 Decidual NCR+ ILC3s also produce IL-22, IL-8 and GM-CSF.64 GM-CSF was found to induce the expression of heparin-binding EGF-like growth factor (HB-EGF) and IL-1 receptor antagonist (IL-1Ra) in neutrophils.65 HB-EGF is a fibrogenic cytokine contributing to a successful pregnancy by regulating the interactions between endometrium and blastocyst, and promoting the angiogenesis at maternal-fetal interface.66 IL1Ra is involved in the trophoblasts invasion during early pregnancy.67 The crosstalk between NCR+ ILC3s and neutrophils at the maternal-fetal interface play a crucial role in maintaining a successful pregnancy.65
Attenuating influenza a virus infection by heparin binding EGF-like growth factor
Published in Growth Factors, 2020
K. M. Lai, B. H. Goh, W. L. Lee
In addition, HB-EGF acts as a crucial mediator of tissue repair and regeneration. In the case of mechanical injury of airway epithelial cells (ACE) associated with certain pulmonary diseases, such as asthma, induction of HB-EGF is essential for ACE repair which is mediator by interleukin 13 (IL-13) ( Allahverdian et al. 2008). On the other hand, it was reported that HB-EGF promotes epithelial-mesenchymal transition (EMT) which is associated with pulmonary fibrosis through induction of N-and E-cadherin, and vimentin expression in epithelial cells (Eapen et al. 2019). Therefore, whether application of HB-EGF enhances the recovery of IAV-induced lung injury or it could worsen the pathology by promoting EMT should further be investigated. In summary, our date provides a novel finding on the attenuation of IAV infection by ligand-induced downregulation of EGFR which promotes the uptake of IAV. Modulation of STAT1 protein by HB-EGF suggests its potential in managing exacerbation of inflammatory response triggered by IAV infection. However, further research is needed to elucidate application of HB-EGF as a clinically relevant option in treating IAV infection.