Phosphoinositide Metabolism
Enrique Pimentel in Handbook of Growth Factors, 2017
Phosphorylation of protein kinase C may contribute to regulate its activity. The enzyme can undergo autophosphorylation at multiple sites,215 and the resulting autophosphorylated kinase has a lower Ka for Ca2+ and a higher affinity for phorbol ester than the nonphosphorylated enzyme, but still requires Ca2+ and phospholipid for maximal activity. Compounds that interact with the catalytic site of protein kinase C, competing with ATP, act as inhibitors of the enzyme in a concentration-dependent manner.216 Casein kinase I, but not casein kinase II, can phosphorylate protein kinase C in the absence of Ca2+ and phospholipids.217 The possible role of autophosphorylation or trans-phosphorylation in the regulation of protein kinase activity in intact cells is not understood.
Nuclear Protein Kinases
Lubomir S. Hnilica in Chromosomal Nonhistone Proteins, 2018
While much of the nuclear protein kinase activity can be separated from the bulk of its nuclear protein substrates, virtually all nuclear protein kinase preparations retain endogenous substrate that can be phosphorylated upon the addition of ATP and Mg++. The possibility that some of this endogenous substrate is the protein kinase itself seems a distinct possibility in view of reports that highly purified cytoplasmic protein kinases catalyze their own autophosphorylation. In the case of type II cyclic AMP-dependent protein kinase, the regulatory subunit is phosphorylated by an intramolecular reaction involving the intact holoenzyme.412–419 The result of this type of phosphorylation is to decrease the affinity of the regulatory subunit for the catalytic subunit, which in essence results in an increased sensitivity of the enzyme to activation by cyclic AMP. Studies on the autophosphorylation of Type I cyclic AMP-dependent protein kinase have led to the conclusion that the catalytic subunit, rather than the regulatory subunit, becomes phosphorylated during autophosphorylation.420 Though analogous modifications of nuclear protein kinases are yet to be unequivocally demonstrated, autophosphorylation is yet another type of potential regulation which should not be overlooked.
Protein Function As Cell Surface And Nuclear Receptor In Human Diseases
Debarshi Kar Mahapatra, Sanjay Kumar Bharti in Medicinal Chemistry with Pharmaceutical Product Development, 2019
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.
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).
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 updated patent review of rearranged during transfection (RET) kinase inhibitors (2016–present)
Published in Expert Opinion on Therapeutic Patents, 2022
Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase encoded by the RET proto-oncogene located on chromosome 10. RET is integral for the development of kidneys and the enteric nervous system during embryogenesis.1 RET is expressed in neural cells and is required for proliferation, differentiation, and survival of these cells[1]. In addition, RET signaling is known to contribute to the regulation and function of hematopoietic cells and spermatogenesis [2,3]. The structure of RET (Figure 1) is similar to other receptor tyrosine kinases, and consists of an intracellular tyrosine kinase domain, a transmembrane domain, and an extracellular domain with four cadherin-like domains and a conserved cysteine region (C609, C611, C618, C620, C630, and C640)[4]. This cysteine region plays a key role in protein conformation and ligand binding [5,6]. RET activating ligands belong to the glial-cell derived neurotrophic factor (GDNF) family of ligands (GFLs) and include GDNF, neurturin, artemin, and persephin[7]. Ligands binds to the GDNF family receptor-α (GFR-α), which then causes dimerization of RET (Figure 1) and subsequent activation through autophosphorylation of the intracellular tyrosine kinase domain (Y687, Y752, Y806, Y809, Y826, Y900, Y905, Y928, Y981, Y1015, Y1062, and Y1062). Following autophosphorylation, multiple signaling pathways (such as PI3K, MAPK, JAK/STAT, and PKC pathways) are activated that regulate survival, differentiation, and proliferation[7].
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