Etiopathogenesis
Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan in Comprehensive Textbook on Vitiligo, 2020
Both peripheral nerve sheath and melanocytes arise from neural crest cells (NCC). These cells migrate from the neural tube to dorsolateral and ventral directions [38] (Figure 5.5). On the one hand, cells with only a dorsolateral trajectory are committed to melanocytic fate; on the other hand, cells with a ventral trajectory are committed to neuronal, glial/melanocyte, or endoneurial fibroblast fate [38]. It has been shown that SOX10+ NCCs fail to initiate the neuronogenesis, adopting a glial pathway to give rise to Schwann cells and melanocytes, highlighting the link between pigmentary disorders (as vitiligo) and neural cells [38]. Neuregulin 1 is an axon-derived growth factor which, when overexpressed, promotes glial fate and suppresses melanocytic activity [39]. Furthermore, melanocytes with the overexpression of embryo retinal epithelium can dedifferentiate back to their unpigmented glial progenitor [39].
Molecular Biology of Lung Cancer as the Basis for Targeted Therapy
Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo in Lung Cancer, 2016
The human epidermal growth factor (EGF) receptor (HER) gene family encodes proto-oncogenes, which belong to the class of receptor tyrosine kinases (16). This family is also named ERBB after the viral erythroblastosis B oncogene and includes the EGF receptor (EGFR/HER1), HER2, HER3, and HER4. These receptors bind ligands such as EGF and neuregulin 1. Binding of ligand induces receptor homo- or heterodimerization, activation of the intrinsic receptor tyrosine kinase, and activation of intracellular signal transduction pathways that simulate proliferation and survival. The EGFR-HER2 heterodimer has been shown to initiate the strongest and most long-lived signaling in NSCLC models (17). Strong EGFR expression is present in 40% to 80% of NSCLC tumor specimens (17). High-level expression of EGFR is also present in premalignant bronchial epithelium, suggesting a role for EGFR in carcinogenesis (17,18). A common mechanism of EGFR over-expression in lung cancer is amplification of the gene copy number (19). Oncogenic mutations of EGFR and HER2, located in the kinase domain and leading to constitutive activation of the kinase, have been reported in up to 35% and 4% of NSCLC specimens, respectively (20). EGFR mutations are mostly found in adenocarcinoma, nonsmokers, and Asian patients. Similar mutations have been detected in the normal respiratory epithelium of up to 43% of patients with EGFR mutant adenocarcinomas and are identical to those seen in tumor specimens from the same patient, suggesting that these mutations may be an early event in carcinogenesis, particularly in never-smokers (21). Mutant EGFR transforms both NIH-3T3 fibroblasts and lung epithelial cells in the absence of EGF, leading to anchorage-independent growth, decreased contact inhibition, and increased tumor formation in immunocompromised mice (22). Mutant cancer cells are strongly dependent on the signal induced by the aberrant EGFR receptor tyrosine kinase (so-called “oncogene addiction”) and undergo apoptosis upon inhibition of the aberrant kinase (23). Taken together, these findings have greatly improved understanding of the critical role that EGFR and other members of the HER family play in lung cancer. The consequences of alterations in EGFR expression or functionality in regard to lung cancer therapy are discussed in a separate chapter.
Basic concepts on melanocyte biology
Electra Nicolaidou, Clio Dessinioti, Andreas D. Katsambas in Hypopigmentation, 2019
Dermal fibroblasts play an active role in modulating melanocyte homeostasis through the secretion of growth factors and cytokines, which act both in a synergistic and sometimes overlapping fashion with respect to the keratinocyte-mediated signaling network. Additionally, some paracrine messengers released by fibroblasts can indirectly target melanocyte functions, inducing the production of biofactors able to either block or stimulate melanocyte activities in keratinocytes. Similar to growth factors and cytokines synthesized by keratinocytes, in this intricate epithelial-mesenchymal interaction, some fibroblastic bioactive messengers act as melanocyte activators, others as inhibitors. The physiological hypopigmented phenotype of the palms and soles has been attributed to increased expression of the Wnt pathway antagonist dickkopf1 (DKK1) in these body areas. This site-specific fibroblast-derived factor exerts a dual action: on the one hand, it suppresses melanocyte growth and melanin synthesis, and on the other, it acts on keratinocytes, decreasing the expression of the proteinase-activated receptor 2 actively involved in the process of melanosome transfer.44 Furthermore, fibroblasts share with keratinocytes the production of TGF-β, with repressive properties on melanocytes.39 However, the largest number of fibroblast-derived messengers exert a positive action on melanocyte activities, acting on their growth, survival, migration, and pigment production. Some of these pro-pigmenting mediators are also produced by epidermal cells, for example, SCF, HGF, and bFGF; others are exclusively of fibroblastic origin. Among the latter, neuregulin-1 has been demonstrated to be highly expressed in fibroblasts of type VI skin, where it positively participates in the regulation of constitutive pigmentation of darker skin.45 Keratinocyte growth factor (KGF) belongs to the family of fibroblast growth factors and represents a further mesenchymal-specific pro-pigmenting paracrine mediator. KGF directly promotes melanosome transfer via activation of its receptor KGFR in keratinocytes. Additionally, it upregulates the synthesis and release of SCF from keratinocytes, thus indirectly promoting melanocyte pro-pigmenting and pro-growing activities. It has been also demonstrated that the treatment with KGF alone or in combination with IL-1α increases melanin production and deposition in pigmented epidermal equivalents and human skin explants.27,46,47 The Wnt modulator secreted frizzled-related protein 2 (sFRP2) has been recently discovered as a further fibroblast-secreted stimulating factor, thanks to its ability to increase the expression levels of MITF and tyrosinase through beta catenin signaling48 (Figure 1.9b).
The significance of the neuregulin-1/ErbB signaling pathway and its effect on Sox10 expression in the development of terminally differentiated Schwann cells in vitro
Published in International Journal of Neuroscience, 2021
Xizhong Yang, Cuijie Ji, Xinyue Liu, Chaoqun Zheng, Yanxin Zhang, Ruowu Shen, Zangong Zhou
Neuregulin-1 (NRG-1) is a member of the family of regulatory proteins that contain the EGF (epidermal growth factor)-like domain. It is a type of transmembrane protein that regulates the growth and development of glial cells and neurons [8]. The functional receptor of NRG is the ErbB receptor, which includes ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4. ErbB is a member of the EGF receptor family of transmembrane tyrosine kinases. Both ErbB2 and ErbB3 receptors are required in the development of SCs, but these two receptors have different effects; ErbB3 can bind with extracellular ligands with high affinity even though it is inactive, while ErbB2 tyrosine kinase activity can activate downstream signaling [9]. Sox10 belongs to the Sox family, members of which contain a DNA binding domain that is similar to the HMG (high mobility group) domain of the SRY transcription factor family [10]. The structure of Sox10 is highly conserved, especially the structure of its functional domains, such as the N-terminal to C-terminal dimerization domain, the HMG domain, and the protein interaction (K2) domain [11]. The Sox gene family is involved in stem cell maintenance, cell differentiation and tissue formation. Sox10 plays an important role in the formation of the neural crest and peripheral nervous system, the maturation and terminal differentiation of SCs, and the differentiation of melanocytes. Sox10 and Oct6 have synergistic effects on the differentiation and development of SCs [12]. In addition, in the central nervous system and the peripheral nervous system, Sox10 is highly expressed in neural crest cells and glial cells.
Treating cardiovascular complications of radiotherapy: a role for new pharmacotherapies
Published in Expert Opinion on Pharmacotherapy, 2018
Nathalie Donis, Cécile Oury, Marie Moonen, Patrizio Lancellotti
Neuregulin-1 is a protein that is expressed by myocytes. It has been involved in several processes including myocardial and conduction system development, cardiac cellular contractility, survival and proliferation, and calcium homeostasis [113]. In a rat model, it has been reported that recombinant human neuregulin-1β (rhNRG-1β) prevented mitochondrial dysfunction and intracellular ATP concentration decrease early after cardiac irradiation. At later stage, rhNRG-1β decreased radiation-induced myocardial fibrosis and cardiomyocyte hypertrophy while preserving cardiac function via the ErbB2-ERK-SIRT1 signaling pathway [114]. rhNRG-1β (NeucardinTM, Zensun) has already been used in a double-blind, randomized phase II clinical trial in patients suffering from chronic heart failure (New York Heart Association functional class II or III). In this trial, a daily dose of rhNRG-1β or placebo was administered to the patients for 10 days, patients were then followed-up for 80 days. rhNRG-1β exhibited encouraging results as it improved cardiac function in patients over time compared to the placebo (increased left ventricular ejection fraction, decreased end-diastolic volume, and end-systolic volume) [115]. Thus, studying the effect of rhNRG-1β in patients who received thoracic RT deserves further consideration.
Bioavailability and Neuroprotectivity of 3-(3, 4-dimethoxy phenyl)-1-4 (methoxy phenyl) prop-2-en-1-one against Schizophrenia: an in silico approach
Published in Journal of Receptors and Signal Transduction, 2019
Venkataramaiah Chintha, Rajendra Wudayagiri
Schizophrenia is a complex psychiatric disorder that is highly heritable with a strong genetic component [1] which include: (1). ‘Potential candidate schizophrenia genes’, which are proposed to be involved in schizophrenia but have not yet been directly investigated for disease involvement; (2). ‘Candidate schizophrenia genes’, which have some direct evidence of disease involvement but for which the evidence is not yet considered to be susceptibility genes; and (3). ‘Schizophrenia susceptibility gene’, for those few genes that have considerable evidence showing contribution to schizophrenia etiology, few schizophrenia susceptibility genes have been identified which include dysbindin (DTNBP1), neuregulin-1 (NRG1), disrupted-in-schizophrenia-1 (DISC1), and Catechol-O-methyl transferase (COMT). Schizophrenia has a high heritability of 80–87% [2], similar to that of bipolar disorder (79–93%) [3], in contrast to other complex diseases such as Alzheimer’s disease (29–79%) [4], asthma (48–79%) [5] and breast cancer (25–50%) [6]. Psychiatric disorders, including schizophrenia, have added complexity in that they rely on non-biological descriptive measures for the purposes of diagnosis, which has shown limited effectiveness for segregating individuals into phenotypically or genotypically homogeneous disease populations [7].
Related Knowledge Centers
- Alternative Splicing
- Epidermal Growth Factor
- ERBB
- Protein Isoform
- Receptor Tyrosine Kinase
- Glycoprotein
- Phosphorylation
- Gene
- Neuregulin
- Her2