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Ataxia Telangiectasia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Located on chromosome 11q22.3, the ATM gene spans 150 kb with 66 exons (including 62 coding and 4 non-coding), and encodes a 3056 aa, 315 kDa protein (ATM), which is a serine/threonine kinase belonging to the phosphatidylinositol 3-kinase family. Structurally, the ATM protein consists of four regions: N-terminal Huntingtin, elongation factor 3, protein phosphatase 2A, and yeast kinase TOR (HEAT) repeat, a FRAP, ATM, TRRAP (FAT) domain, a protein kinase domain and C-terminal FAT-C domain. Located primarily in the nucleus, along with small amounts in the cytoplasm (in association with mitochondria and peroxisomes), and activated by double-stranded DNA break, oxidative stress, hypoxia, hypotonic stress, hyperthermia, chloroquine, and agents affecting chromatin organization, the ATM protein phosphorylates/activates various downstream effectors (including p53, Chk2, MDM2, 53BP1, SMC1, BRCA1, FANCD2, H2AX, c-abl, nibrin, Mre11, KAP1) involved in DNA repair, cell cycle control, apoptosis, and other pathways [6–9].
Gastrointestinal Neuropeptides and Second Messenger Systems
Published in Edwin E. Daniel, Neuropeptide Function in the Gastrointestinal Tract, 2019
Yet another putative signaling mechanism linked to Som receptors was elucidated along with the studies which examined the subcellular distribution of Som receptors. In fractionation studies of rat tissues such as pancreas and intestinal mucosa, a considerable proportion of Som receptors was found to be present in cytosol.73,74 The cytosolic receptors displayed comparable binding affinity for Som as the membrane-bound receptors. The activation of cytosolic receptors was found to stimulate the phosphoprotein phosphatase activity, as documented by the ability of cytosol, in the presence of Som, to hydrolyze phosphorylated histone proteins. Interestingly, similar phosphoprotein phosphatase activity also was demonstrated for membrane-bound receptors in synaptosomal plasma membranes75 and in the pancreatic cell line MIA PaCa-2.76 In the latter experimental model, the activation of Som receptors was shown to dephosphorylate the tyrosine residue in the protein kinase domain of the receptor for epidermal growth factor. It was suggested that this mechanism may account for the ability of Som to antagonize the epidermal growth factor-mediated responses.
Mite Allergens
Published in Richard F. Lockey, Dennis K. Ledford, Allergens and Allergen Immunotherapy, 2014
Enrique Fernández-Caldas, S.L. Inmunotek, Leonardo Puerta, Luis Caraballo, Richard F. Lockey
As happened with genetic studies on allergic diseases including asthma, rhinitis, or atopic eczema, research on the specific IgE response, regardless of whether they are associated with diseases or not, have evolved rapidly, through association studies of small scale based on candidate genes, linkage studies, and genome-wide association studies. The latter have provided more signals of associations in new chromosomal regions and confirmed the role of the MHC on the specific IgE immune responses. For example, Castro-Giner et al. found that SGK493 (PKDCC) in chromosome 2p21, coding for the protein kinase domain-containing protein, is associated with sensitization to D. pteronyssinus and other allergens [222]. Another important association with atopy, as defined by positive serology to D. pteronyssinus, with the gene KIRREL3 was found by Wan et al. [223]. In addition, a genome-wide meta-analysis from four cohorts shows that the HLA region is strongly associated with grass sensitization [224]. The use of whole-genome sequencing for this research will provide much more information on genes that control the specificity and intensity of specific IgE response. This, in turn, will better define the profile of genes required to display the clinically manifest disease, as sensitization to allergens (atopy) does not necessarily induces allergic symptoms.
An updated patent review of anaplastic lymphoma kinase inhibitors (2018–2022)
Published in Expert Opinion on Therapeutic Patents, 2023
Deyi Ma, Mengrao Guo, Xin Zhai
Physiologically, ALK contributes to the development of the embryonal nervous system, and its expression decreases after birth. However, ALK protein kinase domain will be overactivated once ALK fusion occurs, and then the cells will uncontrollably proliferate, survive, differentiate, migrate, and lead to cancers ulteriorly. For instance, the fusion of ALK gene (2p23) and NPM gene (5q35) occurred in approximately 70–80% of all ALK-positive ALCL patients [9,10] and in patients with inflammatory myofibrosarcoma (IMT), approximately 50% of morbidity displayed fusion of chromosome 2’s short arm (where ALK is located) to TPM3 or to TPM4 [11,12]. In 2007, Mano’s group revealed that the chromosomal rearrangement involving the ALK and echinoderm microtubule-associated protein like 4 (EML4) genes showed potent transforming activity in NSCLC [13]. Furthermore, diffuse large B-cell lymphoma (DLBCL) is associated with CLTC-ALK fusion (t(2;17)(p23;q23) translocation results in the CLTC-ALK fusion protein) [14,15].
Is neurotrophin-3 (NT-3): a potential therapeutic target for depression and anxiety?
Published in Expert Opinion on Therapeutic Targets, 2020
A. S. de Miranda, J. L. V. M. de Barros, Antonio Lucio Teixeira
Neurotrophins exert their biological actions by binding with high or low affinity to different subtypes of Trks. For instance, NT-3 binds to TrkC with high affinity but can also bind to TrkA and TrkB with lower affinity under high concentration. On the other hand, BDNF and NT-4/5 bind preferentially to TrkB, whereas NGF shows high affinity for TrkA [12,13]. The extracellular domain of each of the Trk receptors consists of a cysteine-rich cluster followed by three leucine-rich repeats, another cysteine-rich cluster, and two immunoglobulin-like domains [13,14]. The major site at which neurotrophins interact with these receptors is in the membrane-proximal immunoglobulin-like domain, triggering receptor dimerization, and transphosphorylation of intracellular tyrosine residues in its cytoplasmic domain and kinase activation [12,13]. After phosphorylation, Trk receptors act as scaffolding molecules recruiting adaptor proteins, like the protein kinase domain (Src) homologous and collagen-like (Shc) adaptor protein, that couple the receptor to downstream signaling pathways, such as extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and phospholipase C-γ (PLC-γ), modifying gene expression and neuronal functioning. Importantly, Trk receptors are specifically activated by the mature and not the pro-forms of the neurotrophins [12–14].
Current discovery strategies for hepatocellular carcinoma therapeutics
Published in Expert Opinion on Drug Discovery, 2020
Qiuzi Dai, Cunlong Zhang, Zigao Yuan, Qinsheng Sun, Yuyang Jiang
The epidermal growth factor receptor (EGFR) is a transmembrane receptor that belongs to the family of receptor tyrosine kinases (RTK), also known as ErbB1 or HER-1 [30–33]. It is a typical RTK with an extracellular ligand-binding region, a transmembrane region, and an intracellular protein kinase domain. The overexpression of EGFR has been demonstrated in many human cancers, such as breast cancer, stomach cancer, esophageal squamous carcinoma, hepatocellular carcinoma and so on. Several ligands could specifically bind EGFR including epidermal growth factor (EGF), transforming growth factor (TGF-α), amphiregulin (AR), epiregulin (EREG), betacellulin (BTC), heparin-binding EGF (HB-EGF) and epigen (EPGN). The activation of EGFR by these ligands has strong proliferative effects on hepatocytes. As reported [34–36], EGFR overexpression is account for 68% in human HCC.