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Index A endothelial cell-derived tumors, 396 Abl, kinase modulation by SH2 metastasis studies, 394 allosteric activation, 39–40 tumor vascularization, 393–394 inhibition by intramolecular interactions, 38–39 development Acetylcholine receptor (AChR) endothelial cell expression of receptors muscle-specific kinase interactions, 265–268 Tie receptors, 392–393 myasthenia gravis autoantibodies, 271–272 vascular endothelial growth factor AChR. See Acetylcholine receptor receptor, 391–392 Acute myeloid leukemia, Kit role, 217 overview, 387–388 ADAM proteases inhibition for therapy, 396–400 domain structure, 119–120 lymphangiogenesis defects in lymphedema, 375 ephrin cleavage, 312 prospects for study, 400 epidermal growth factor receptor ligand therapeutic angiogenesis, 394–395 shedding role, 120–121 tip and stalk cell expression of receptor shedding tyrosine kinases, 389 stimuli, 121–122 vascular malformations, 396 tetraspanins in spatial control, 122–123 Angiopoietins ADAM10 Ang2 signals in inflammation, 395–396 ephrin proteolysis, 126 angiogenesis role, 391 platelet-derived growth factor receptor functional overview, 287–288 ligand proteolysis, 126 inhibitor therapy, 399–400 ADAM12, ErbB2 expression regulation, 140 knockout mouse, 392–393 ADAM17 (TACE) structure, 288–289 activity regulation in plasma membrane, 122 vascular endothelial growth factor receptor ErbB-4 as substrate, 50–51, 68–69 signaling cross talk, 234 trafficking regulators, 123 Apoptosis, TAM receptors in cell clearance, 373–374 Agrin, Lrp4 binding, 265, 269–270 Atherosclerosis, platelet-derived growth factor Akt receptor role, 214 ephrin receptor signaling, 310–311 Axl. See TAM receptors Grb2 in signaling, 38 insulin receptor signaling, 412–413 insulin resistance defects, 420 B MET signaling, 437 BCR-ABL RET signaling, 280–281 chronic myelogenous leukemia, 17–18 TAM receptor signaling, 371 therapeutic targeting, 18 Alk. See Anaplastic lymphoma kinase Bevacizumab, 235 a-Secretase. See ADAM17 Bioinformatics, tyrosine phosphorylation, 23 AMSH, endosomal sorting role, 86 Breast cancer, RET mutations, 461 Amyotrophic lateral sclerosis, ephA4 mutations, 317 Breathless, Drosophila studies, 343–344 Anaplastic lymphoma kinase (Alk) BY kinases, features, 19 Drosophila function, 347–349 therapeutic targeting, 18 Angiogenesis. See also Angiopoietins; Vascular endo- C thelial growth factor receptor Cad96Ca, Drosophila wound repair, 353 Ang2 signals in inflammation, 395–396 Cancer blood versus lymphatic vasculature, 388–389 angiogenesis cancer endothelial cell-derived tumors, 396 469 Index Cancer (Continued) Diabetes. See Insulin resistance metastasis studies, 394 Diacylglycerol (DAG), insulin resistance role, 420 tumor vascularization, 393–394 Discoid domain receptor (DDR), ephrin receptor mutations, 316–317 Drosophila studies, 350 Kit role Dok-2, PTB domain, 37 acute myeloid leukemia, 217 Dok-7, 42, 270–272 gastrointestinal stromal tumor, 217 Doughnut, Drosophila studies, 352 lung cancer, 217–218 Drosophila melanoma, 217 anaplastic lymphoma kinase function, 347–349 ligand shedding dysregulation, 126–127 Cad96Ca in wound repair, 353 lung cancer epidermal growth factor receptor discoid domain receptor function, 350 mutations and therapeutic targeting, ephrin receptor function, 354 166, 168 epidermal growth factor receptor MET therapeutic targeting in cancer, 443–444 functional overview, 341–342 platelet-derived growth factor receptor tumor cell ligand proteolysis overactivity, 213–214 overview, 116–117 RET mutations. See RET trafficking regulation, 117–118 Ror studies, 328 fibroblast growth factor receptors TAM receptor defects, 378–379 Breathless, 343–345 Caspases, intracellular domain cleavage from receptor Heartless, 342–343 tyrosine kinases, 55 insulin receptor function, 345–347 Cbl neurotrophic receptor kinase function, 349 MET signaling, 439 Offtrack function, 350–351 mutation in cancer, 42 overview of receptor tyrosine kinases and ligands, receptor endocytosis role, 82–83 337–339 SH2 domain, 35 prospects for receptor tyrosine kinase studies, Ceramide, insulin resistance role, 420 356–357 Clathrin-mediated endocytosis. See Endocytosis, Pvr function, 354–356 receptor tyrosine kinases RET function, 353 CMS. See Congenital myasthenic syndrome rhomboids, 116–117, 125 Colony-stimulating factor-1 receptor, intracellular Ror function, 326, 349 domain cleavage by g-secretase, 53–54 Ryk receptors Congenital myasthenic syndrome (CMS), gene Derailed, 351–352 mutations, 42 Derailed 2, 352–353 Crizotinib, receptor tyrosine kinase inhibition, 18 Doughnut, 352 Crk Sevenless in cell fate specification in eye and testes, ephrin receptor signaling, 308 340–341 platelet-derived growth factor receptor Tie-like receptor tyrosine kinase function, 356 binding, 210 Torso role in anterior/posterior patterning and SH2/SH3 domains, 9 metamorphosis, 339–340 signaling complex assembly, 38 DUSP, 141 Cryoelectron microscopy, phosphotyrosine protein structure, 22, 26 E EGFR. See Epidermal growth factor receptor D Endocytosis, receptor tyrosine kinases DAG. See Diacylglycerol clathrin-independent endocytosis, 79–80 DC. See Dendritic cell clathrin-mediated endocytosis, 79 DDR. See Discoid domain receptor cytoplasmic domain sequence motifs, 80 Degenerate peptide library, tyrosine kinase target endosomal sorting. See Endosomal sorting, identification, 22–23 receptor tyrosine kinases Dendritic cell (DC), TAM receptor function, 375–376 half-life range, 77 Derailed miscellaneous mechanisms, 84 Drosophila studies, 351–352 NEDD4 role, 83–84 Wnt signaling, 330–332 pathways, 78–80 Derailed 2, Drosophila studies, 352–353 prospects for study, 88 470 Index receptor ubiquitination role, 80–83 therapeutic targeting, 295 signaling effects Epidermal growth factor receptor (EGFR). cell adhesion regulators, 100 See also specific receptors hypoxia modulation, 99–100 dimerization, 5–8 ligand concentration effects on entry routes endocytosis, 79–84, 99–100 and intracellular fate, 97–99 endosomal sorting, 87 overview, 95–97 family characteristics, 161–163 spatial regulation of internalization, 100–101 history of study, 1, 3–5, 15, 17–18 stress factor modulation, 99 kinase domain activation, 164, 166–167 steps, 77–79 ligand concentration effects on entry routes ubiquitin-binding proteins in CCPs, 84 and intracellular fate, 97–98 Endoplasmic reticulum (ER) ligand proteolysis receptor tyrosine kinase signal modulation, 107–108 ADAMs in ligand shedding, 120–121 unfolded protein response in insulin resistance, 422 Drosophila Endosomal sorting, receptor tyrosine kinases overview, 116–117 coreceptor-modulated sorting of ligand–receptor trafficking regulation, 117–118 complexes, 103 mammalian ligands, 118–119 ESCRT sorting model, 85–86 ligand-dependent sorting, 101–102 ligand-dependent sorting of receptor, 101–102 linkage between intracellular and extracellular multivesicular body sorting model, 85–87 regions, 172–173 overview, 85 lung cancer mutations and therapeutic targeting, receptor-mediated sorting of ligands, 102–103 166, 168 recycling of receptors. See Recycling, receptor negative cooperativity, 171–173 tyrosine kinases phospholipase Cg association, 9 signaling effects phosphorylation sites, 9 compartmentalization of signaling, 107 recycling, 87–88 endoplasmic reticulum in signal modulation, signaling 107–108 cross talk, 9–10, 134–137, 142–143 intracellular signal delivery via endosomes, 105 feedforward loops, 137–138 microvesicle propagation of signals, 108 positive and negative feedback regulation signal amplification, 105–107 overview, 138–139 signaling endosomes, 105 receptor level, 139–140 Ephrin, proteolysis, 126, 298–299, 313 signaling level, 140 Ephrin receptor transcription, 140–142 angiogenesis role, 388 prospects for study, 144–145 Drosophila studies, 354 spatial signal propagation, 143–144 Ephrin receptor transduction, 179, 181 activation ER. See Endoplasmic reticulum kinase, 297–298 ErbB receptors transmembrane domain role, 297 kinase domain activation, 164, 166–167 classification, 305 ligands clustering and activation, 296–298, 307 receptor dimerization induction, 164–165 dephosphorylation, 315 types and processing, 163–164 ephrin-independent activities, 314–315 linkage between intracellular and extracellular functional overview, 292–294, 305–306 regions, 172–173 internalization and proteolysis, 312–314 lung cancer mutations and therapeutic intracellular domain cleavage by g-secretase, 53 targeting, 166, 168 ligand recognition and binding, 294–295 negative cooperativity, 171–173 mutation and disease, 316–317 plasma membrane distribution, 193–197 prospects for study, 299, 317 spatiotemporal organization signaling cluster size studies with conventional ephrin-mediated cis attenuation, 314 microscopy, 181–182 forward signaling, 306–311 fluorescence resonance energy transfer reverse signaling, 311–312 activation and signaling, 188–189 termination, 298–299 protein–protein interactions, 184–186 structure, 305–306 high-resolution imaging, 182–184 471 Index ErbB receptors (Continued) D3 and ligand specificity, 246–247 prospects for study, 189 dimerization, 8 single-molecule studies of protein–protein Drosophila interactions, 186–188 Breathless, 343–345 techniques for study, 179–180 Heartless, 342–343 structure heparan sulfate binding, 250–252 carboxy-terminal tail, 170–171 kinase extracellular juxtamembrane region, 168–169 autophosphorylation, 255–257 intracellular juxtamembrane region, 169–170 regulation mechanism, 253–255 transmembrane domain, 168 Klotho in signaling, 252–253 ErbB1 ligand–receptor contacts, 246 nuclear trafficking
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  • Amplification of the Human Epidermal Growth Factor Receptor 2 (HER2) Gene Is Associated with a Microsatellite Stable Status in Chinese Gastric Cancer Patients

    Amplification of the Human Epidermal Growth Factor Receptor 2 (HER2) Gene Is Associated with a Microsatellite Stable Status in Chinese Gastric Cancer Patients

    387 Original Article Amplification of the human epidermal growth factor receptor 2 (HER2) gene is associated with a microsatellite stable status in Chinese gastric cancer patients He Huang1#, Zhengkun Wang2#, Yi Li2, Qun Zhao3, Zhaojian Niu2 1Department of Gastrointestinal Surgery, The First Hospital of Shanxi Medical University, Shanxi, China; 2Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China; 3Department of Gastrosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China Contributions: I) Conception and design: Z Niu, Q Zhao, H Huang; (II) Administrative support: Z Niu, H Huang, Z Wang; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: Z Wang, Q Zhao; (V) Data analysis and interpretation: Z Niu, H Huang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. #These authors contributed equally to this work. Correspondence to: Zhaojian Niu. Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao 260003, China. Email: [email protected]; Qun Zhao. Department of Gastrosurgery, The Fourth Hospital of Hebei Medical University, No. 12 Jiankang Road, Shijiazhuang 050011, China. Email: [email protected]. Background: Gastric cancer (GC) is one of the most common cancers worldwide. However, little is known about the combination of HER2 amplification and microsatellite instability (MSI) status in GC. This study aimed to analyze the correlation of HER2 amplification with microsatellite instability (MSI) status, clinical characteristics, and the tumor mutational burden (TMB) of patients. Methods: A total of 192 gastric cancer (GC) patients were enrolled in this cohort. To analyze genomic alterations (GAs), deep sequencing was performed on 450 target cancer genes.