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Neurofibromatosis Types 1 and 2
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The gene underlying the molecular pathogenesis of NF2 is NF2 on chromosome 22q12.2, which was identified in 1993. The NF2 gene encodes a membrane-cytoskeleton scaffolding protein known as “merlin” (for moezin-ezrin-radixin-like protein, due to its relationship to the moesin [membrane organizing extension spike protein]−erzin [cytovillin]−radixin family of cytoskeleton-associated proteins) or “schwannomin” (in recognition of its role in preventing schwannoma formation), which consists of three structurally distinct regions: (i) a N-terminal FERM (four-point−one, ezrin, radixin, and moesin) domain, (ii) a α-helical coiled-coil domain, and (iii) a C-terminal hydrophilic tail. Of the two isoforms produced, the longer form (merlin or merlin 1595aa) possesses an extended C-terminal tail (encoded by exon 17) that is involved in intramolecular binding between the amino-terminal FERM domain and the C-terminal hydrophilic tail, yielding a closed or functional state, and the shorter form (merlin 2) results from an alternatively spliced exon 16 ending in a stop codon and contains 11 unique residues following amino acid 579, without the C-terminal residues, yielding an open or nonfunctional state. By linking actin filaments via its N-terminal domain containing glutathione S-transferase to cell membrane or membrane glycoproteins, merlin acts as a critical regulator of contact-dependent inhibition of proliferation and function at the interface, and contributes to the maintenance of normal cytoskeletal organization, the modulation of cellular motility, attachment, remodeling, and spreading, and the regulation of growth (tumor suppression) through its ability to stabilize cadherin-dependent cell-to-cell junctions, to inhibit the effects of receptor tyrosine kinases (RTK) at the cell membrane, and to facilitate endocytic trafficking of RTK. Merlin deficiency can increase the signaling of the ErbB/EGFR family RTK and activation of prosurvival and proliferation pathways via RAS modulation (due to its many shared targets with NF1), leading to unmediated progression in the cell cycle and subsequent tumorigenesis [16].
Detecting novel mutations and combined Klinefelter syndrome in Usher syndrome cases
Published in Acta Oto-Laryngologica, 2019
Xiaohong Li, Shasha Huang, Yongyi Yuan, Yu Lu, Dejun Zhang, Xiaobin Wang, Huijun Yuan, Weiju Han, Pu Dai
Based on amino acid conservation and a structural analysis, all four novel mutations identified in probands 1 and 2 involved evolutionarily conserved amino acids. They were all located in important functional domains of the protein and are suspected to disrupt normal MYO7A function. The mutations c.3080T > C (p.L1027P) and c.3576G > A (p.W1192X) identified in proband 1 were located in the first MyTH4 domain. The two mutations c.1959delG (p.V653fs) and c.4152G > C (p.K1384N) identified in proband 2 were located in the motor head domain and the first FERM domain, respectively. The motor domain plays an important role in regulating ATP hydrolysis and interacting with actin filaments [14]. Myosin VIIa interacts with other USH1 proteins via the MyTH4 and FERM domains, and participates in shaping the hair bundles in the inner ear [15].
Selective Tyk2 inhibitors as potential therapeutic agents: a patent review (2015–2018)
Published in Expert Opinion on Therapeutic Patents, 2019
Xingrui He, Xiabin Chen, Hancheng Zhang, Tian Xie, Xiang-Yang Ye
Janus kinases (or Jaks) is an intracellular, non-receptor tyrosine kinase family consisting of four different subtypes, namely Jak1, Jak2, Jak3, and Tyk2. Jak1, Jak2, and Tyk2 are ubiquitously expressed, while Jak3 is mainly localized in hematopoietic cells. This family protein is relatively large in size (ranging from 120 to 140 kDa), with defined structure featuring seven distinct regions called Janus homology domain 1–7 (or JH1–7). JH1 is the first region from C-terminal and is kinase catalytic domain, where the ATP binding pocket is located and functioning during phosphorylation process. JH2 is next to JH1, bears structure similarity to JH1, but with several key amino acid residues altered from those in the catalytic domain. Hence, JH2 lacks catalytic function of JH1 and is termed pseudokinase domain. The JH3-JH4 domains of Jaks share homology with Src-homology-2 (SH2) domains. The amino terminal (NH2) end (JH4-JH7) of Jaks is called a FERM domain (short for band 4.1 ezrin, radixin and moesin); this domain is also found in the focal adhesion kinase (FAK) family and is involved in association of Jaks with cytokine receptors and/or other kinases [1].
Filgotinib for the treatment of Crohn’s disease
Published in Expert Opinion on Investigational Drugs, 2018
Remi Labetoulle, Stephane Paul, Xavier Roblin
Mammalian JAKs are composed of four domains: the N-terminal domain is the FERM domain (interaction with membrane receptors and promoting kinase function); then comes the SH2-like domain (membrane receptor interaction); third is the pseudokinase domain (acting as a chaperone in limiting unwarranted kinase activity); finally in the C-terminal domain is the kinase domain, containing the tyrosine residues necessary for trans-activation, as well as the catalytic elements used in the tyrosine-phosphorylation of receptors, either other JAK members or STAT factors [32]. The pseudo-kinase domain is the most prone to oncogenic mutations, which unleash JAK hyperactivity by lifting its inhibitor status.