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Chemical– and Drug–Receptor Interactions
Published in Frank A. Barile, Barile’s Clinical Toxicology, 2019
The receptor tyrosine kinase consists of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. This class of receptor is associated with signaling by insulin, transforming growth factor-αα (TGFαα), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and many other trophic hormones. Ligand (hormone) binding to the receptor results in receptor dimerization, which triggers the tyrosine kinase activity in the intracellular domain. This causes autophosphorylation of the receptor and the induction of signal transduction cascades implicated in cell proliferation and survival. Figure 11.2 illustrates the mechanism of activation of the EGF receptor, a representative tyrosine kinase receptor.
Protein Function As Cell Surface And Nuclear Receptor In Human Diseases
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
Urmila Jarouliya, Raj K. Keservani
Many growth factors, such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and fibroblast-derived growth factor (FGF) and insulin receptor (IR) functions through tyrosine kinase activity. Activation of tyrosine kinase receptors takes place by dimerization of the receptors followed by autophosphorylation, which mainly occurs when one receptor molecule phosphorylates the other molecule in the dimer. The autophosphorylation occurs on two different classes of tyrosine residues. The autophosphorylation takes place on a conserved tyrosine residue within the kinase domain. The phosphorylation of the tyrosine residue at this end-neighboring site leads to an increase in the kinase activity and precedes phosphorylation of other sites in the receptor or substrates in cases of receptors for insulin and hepatocyte growth factor (HGF) [54, 55]. Some autophosphorylation sites are normally localized outside the kinase domains and create docking sites for downstream signal transduction containing SH2 domains.
Mechanisms of Anticancer Drugs
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
Epidermal growth factor receptor (EGFR) biology is a 170 kD transmembrane protein composed of an extracellular ligand-binding domain, a transmembrane lipophilic region and an intracellular protein tyrosine kinase domain (Figure 4.4). When a substrate binds to the receptor, the ligand-receptor complex dimerizes and is internalized by the host cell. This activates an intracellular protein kinase by autophosphorylation, which in turn activates signal transduction pathways, influencing cell function. This can lead to cell proliferation, as well as invasion and metastasis.
Resveratrol inhibits neural apoptosis and regulates RAX/P-PKR expression in retina of diabetic rats
Published in Nutritional Neuroscience, 2022
Kaihong Zeng, Yuan Wang, Lujiao Huang, Yi Song, Xuemei Yu, Bo Deng, Xue Zhou
PKR was initially identified as a double-stranded RNA-activated protein in response to virus infection. Subsequent studies have found that PKR can be activated by various physiochemical stresses in addition to double-stranded RNA. PKR activation is mediated by direct binding with its protein activator, PACT/RAX. Therefore, PACT/RAX acts as an important stress sensor protein in response to diverse stressful conditions. Upon activation, PKR undergoes homodimerization and autophosphorylation. After autophosphorylation, PKR catalyzes the phosphorylation of its downstream substrates. Phosphorylated PKR also translocates into the nucleus from the cytosol to regulate the expression of various genes. PKR not only plays an important role in apoptosis under stress conditions but also has recently been shown to be an activator of inflammasome to regulate cellular inflammatory response [16, 17]. Qi et al. (2014) revealed that PKR was an important mediator of ethanol-induced apoptosis and was activated upon binding with RAX. They also confirmed that overexpression of RAX enhanced PKR activation as well as cellular sensitivity to ethanol [18]. In contrast, blocking the binding of RAX and PKR activation as well as cell apoptosis. In the present study, we found that the expression of RAX and phosphorylated PKR (P-PKR) was increased in the retina of diabetic rats, which is down-regulated by RSV administration.
An appraisal of vascular endothelial growth factor (VEGF): the dynamic molecule of wound healing and its current clinical applications
Published in Growth Factors, 2022
Aakansha Giri Goswami, Somprakas Basu, Farhanul Huda, Jayanti Pant, Amrita Ghosh Kar, Tuhina Banerjee, Vijay Kumar Shukla
VEGFR-1, 2, and 3 are transmembrane proteins with tyrosine kinase activity (Olofsson et al. 1998). The exact mechanism of VEGF-induced intracellular activity is still a subject of intense study. Broadly, it appears that VEGF binding with the extracellular domains causes autophosphorylation of the receptor. This leads to activation of phospholipase Cγ, which activates protein kinase C and catalyzes the conversion of phosphatidylinositol 4,5-biphosphate (PIP2) to inositol 1,4,5-triphosphate (IP3) and diacylglycerol (Shibuya 2001). Finally, MAP-kinase (mitogen-activated protein kinase) activation leads to gene expression (Waltenberger et al. 1994). Although VEGFR-1 has the highest affinity for VEGF, its activation has very weak transcription effects, which puts a question mark on its true role in stimulating angiogenesis. On the other hand, VEGFR-2 is expressed significantly more than its counterpart and demonstrates 10 times more tyrosine kinase activity, which makes VEGFR-2 as the main mediator of VEGF function and a probable target for pharmacological intervention (Waltenberger et al. 1994). On the other hand, binding to its soluble receptors does not induce gene transcription and limits VEGF activity. It appears that VEGFR-1 and sVEGFR-1, 2 control VEGF overexpression and help in maintaining an angiogenic homeostasis.
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).