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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The type I RTK kinase family consists of four distinct but closely related receptors: epidermal growth factor receptor 1 (EGFR, ErbB1, Her1), 2 (HER2, ErbB2), 3 (Her3, ErbB3), and 4 (HER4, ErbB4). In response to the binding of various ligands, these kinases undergo heterodimerization and homodimerization, resulting in the activation of numerous growth factor signaling pathways. Therefore, inhibiting these activated pathways can lead to an antitumor effect. In a large variety of tumor types the over-expression and/or constitutive activation of EGFR and HER2 are often observed and frequently correlate with poor clinical prognosis. For example, in gastric cancer approximately 10% of tumors have amplification of the HER2 gene. Therefore, the HER-family of receptors has been a key target for the development of anticancer therapeutics.
Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
Figure 2.9 captures the complexity of the combinatorial DAR signaling. Panel A depicts the canonical signaling pathways by D1-like and D2-like receptors, which are linked to Gs/olf and Gi/o respectively, and stimulate and inhibit AC. Dimerization and oligomerization increase the complexity of DAR signaling by acquiring pharmacological and functional properties that are distinct from those of the individual monomers [16]. As depicted in Figure 2.9, panel B, D1R-D2R heterodimers have been reported to be linked to the Gq subunit, which regulates phospholipase C (PLC), a class of membrane-associated enzymes that cleave phospholipids. The 13 mammalian PLCs are classified into six isotypes (β, γ, δ, ε, ζ, η) according to structure, with each having unique as well as overlapping controls over its expression and subcellular distribution. The regulators of each PLC vary, but typically include heterotrimeric G protein subunits, protein tyrosine kinases, small G proteins, Ca2+, and phospholipids. Activation of PLC stimulates the production of inositol triphosphate (IP3) and diacylglycerol (DAG), which regulate intracellular calcium and activate PKC. Further permutations of the signaling pathways can result from DAR heterodimerization with nonhomologous receptors.
Epidermal Growth Factor Receptor Inhibition in Non–Small Cell Lung Cancer
Published in Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo, Lung Cancer, 2016
Antonio Jimeno, Manuel Hidalgo
The epidermal growth–factor receptor (EGFR, HER1) is a member of the HER family of membrane receptors (HER1–4). The other members are HER2 (also termed ErbB2 or HER2/neu), HER3 (also termed ErbB3), and HER4 (also termed ErbB4). These receptors share the same molecular structure with an extracellular, cysteine-rich, ligand-binding domain, a single α-helix transmembrane domain, and an intracellular domain with tyrosine–kinase (TK) activity in the carboxy-terminal tail (excepting the HER3) (1). The TK domains of HER2 and HER4 show an 80% homology to that of the EGFR (2). Epidermal growth factor (EGF), transforming growth factor-α (TGF-α), and amphiregulin bind exclusively to the EGFR, whereas betacellulin and epiregulin bind both EGFR and HER4. Ligand binding induces EGFR homodimerization as well as heterodimerization with other types of HER proteins (3,4). HER2 does not bind to any known ligand, but it is the preferred heterodimerization partner for EGFR after ligand-induced activation (5). EGFR/EGFR homodimers are unstable, whereas EGFR/HER2 heterodimers are stable and recycle more rapidly to the cell surface (6).
The effect of ionomycin-induced oocyte activation on multiple morphological abnormalities of the sperm flagella
Published in Systems Biology in Reproductive Medicine, 2023
Zhiren Liu, Yujia Guo, Xingting Chen, Chen Lin, Xinxin Guo, Mingting Jiang, Qicai Liu
Day 6 embryos with blastulation failure are suitable for the comparison. Through the transcriptome analysis of day 6 embryos, GO analysis showed that AOA had effects on the terms of ‘protein-DNA complex’, ‘nucleosome’, and ‘DNA packaging complex’. It indicated that AOA had an effect on the chromosome structure of the day 6 embryo. The change in chromosome structure can further affect transcriptional regulation and selective expression of genes. Cell differentiation depends on gene-specific expression. Therefore, cell differentiation may also be affected by AOA. It may be why the blastocysts of AOA groups had more differentiation failure cells. In addition, in the ‘protein heterodimerization activity’ term, except for the genes involved in chromosome structure, most of the rest of the genes are involved in transcriptional regulation. These genes included USF1, NFYB, METTL3, LSM6, GTF2A1, FMR1, CREB3L3, CEBPB, and BHLHE40 (Table 2 and Supplementary Table 3). METTL3 has been shown to be involved in the differentiation of embryonic stem cells (Geula et al. 2015). Therefore, AOA also has a direct effect on transcriptional regulation.
The roles of epidermal growth factor receptor in viral infections
Published in Growth Factors, 2022
To date, eight EGFR ligands have been identified: EGF, heparin-binding EGF-like growth factor (HB-EGF), transforming growth factor-α (TGFα), amphiregulin (AR), betacellulin (BTC), epiregulin (EPI), connective tissue growth factor (CTGF) and epigen (Harris 2003). EGFR ligands are initially presents as type 1 transmembrane proteins. They are processed to a soluble form and released to extracellular matrix through proteolytic cleavage mediated by matrix metalloproteases (MMPs). However, some ligand precursors like HB-EGF, TGFα, AR and BTC are biologically active, and they function as cell-to-cell adhesion proteins that induce juxtacrine activation of EGFR. Binding of ligands trigger a large conformational change in the extracellular domain and promotes homo- or heterodimerization of the receptors. Subsequently, autophosphorylation of intracytoplasmic tyrosine kinase domain occurs. The phosphorylated tyrosine kinase residues serve as the binding sites for cytosolic proteins containing Src homology 2 (SH2) domain or phospho-tyrosine binding (PTB) motifs which mediate the activation of multiple signal transduction pathways (Mitchell, Luwor, and Burgess 2018).
Investigational fibroblast growth factor receptor 2 antagonists in early phase clinical trials to treat solid tumors
Published in Expert Opinion on Investigational Drugs, 2019
Dan Wang, Li Yang, Weina Yu, Yi Zhang
FGFR-targeted drugs have exhibited favorable clinical responses and a manageable safety profile in FGFR2 fusion-positive ICCA, advanced-stage clonal FGFR2 gastric cancer, FGFR-amplified NSCLC, and FGFR-mutant bladder, urothelial, breast, and biliary duct cancer, FGFR2-alteration bladder, urothelial, glioblastoma, urothelial, endometrial, breast, and biliary duct cancer. Structural similarities with other molecules in the FGFR family, including FGFR1 and FGFR3, limit the specificity of FGFR2-targeted therapy. Hence, further studies are required to focus on molecular alterations in FGFR2 and its activated pathway, thus facilitating better treatment outcomes with the targeted therapies. Although FGFR2 is an oncogene [137,156], it also displays tumor suppressor effects under different cellular contexts and in different isoforms [10,26,157,158]. Several studies on different FGFR2 isoforms have reported conflicting results regarding its clinical roles [26,159]. More effective methods to detect FGFR2 isoforms and their response to different interruption pathways are needed. Moreover, FGFR heterodimerization is a method of signal amplification and diversification, which enhances receptor activation and downstream signaling [160,161]. The potential for FGFR heterodimerization represents another potential obstacle, for which new methods are required to characterize heterodimerization.