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 and function, 56–57, 73 prospects for study, 257 plasma membrane distribution, 195 structure, 242–246 signaling Fibroblast growth factor receptor 1 (FGFR1) filopodia, 198–200 endosomal signaling, 107 potentiation, 200–201 intracellular domain cleavage by granzyme B, 55 without ligand, 20 ligand-dependent sorting, 102 splicing-dependent fragments, 56 nuclear trafficking and function, 59, 74 structure, 181, 197–199 Fibroblast growth factor receptor 2 (FGFR2) ErbB2 ligand-dependent sorting, 102 carboxy-terminal fragment cleavage, 55–56 nuclear trafficking, 59 nuclear trafficking and function, 57–58, 71 Fibroblast growth factor receptor 3 (FGFR3), plasma membrane distribution, 195–196 intracellular domain cleavage by therapeutic targeting, 18 g-secretase, 55 ErbB3 Fibroblast growth factor receptor 4 (FGFR4), nuclear trafficking and function, 57–58, 71–72 receptor-mediated sorting of plasma membrane distribution, 196 ligand, 103 ErbB4 Fibroblast growth factor receptor substrate 2 (FRS2) intracellular domain cleavage by g-secretase, 50–53 PTB domain, 37 nuclear signaling, 68–70 recruitment and activation of signaling Erlotinib, lung cancer management, 166 molecules, 10 ESCRT, endosomal sorting model, 85–87 Flt-1. See Vascular endothelial growth factor receptor Evolution Fluorescence resonance energy transfer (FRET) protein tyrosine phosphatases, 21 ErbB receptor receptor tyrosine kinases, 20–21 activation and signaling, 188–189 tyrosine kinases, 19–20 protein–protein interactions, 184–186, 197–199 kinase assays, 23–24 F subcellular localization of tyrosine FGF. See Fibroblast growth factor phosphorylation, 25 FGFR. See Fibroblast growth factor receptor Foxo1, insulin receptor signaling, 413 FGFR1. See Fibroblast growth factor receptor 1 FRET. See Fluorescence resonance energy transfer FGFR2. See Fibroblast growth factor receptor 2 Frizzled, Wnt ligands, 325–326 FGFR3. See Fibroblast growth factor receptor 3 FRS2. See Fibroblast growth factor receptor FGFR4. See Fibroblast growth factor receptor 4 substrate 2 Fibroblast growth factor (FGF) receptor ligand-binding specificity mechanisms FGF1 subfamily, 247–249 G FGF7 subfamily, 247 Gab1, MET signaling, 436–437 FGF8 subfamily, 249–250 g-Secretase, intracellular domain cleavage from structure–function relationships, 242–243 receptor tyrosine kinases types, 242 colony-stimulating factor-1 receptor, 53–54 Fibroblast growth factor receptor (FGFR) Ephrin-B2 receptor, 53 alternative splicing ErbB-4, 50–53 D1 and D1–D2 linker and receptor fibroblast growth factor receptor 3, 55 autoinhibition, 252–253 insulin receptor, 54

472 Index

insulin-like growth factor-1 receptor, 54 I Met, 55 ICD. See Intracellular domain overview, 49–51 IGF-1R. See Insulin-like growth factor-1 receptor protein tyrosine kinase 7, 55 Imatinib, receptor tyrosine kinase inhibition, 18 Ryk, 54–55 Insulin-like growth factor-1 receptor (IGF-1R) Tie1, 54 endosomal sorting, 87 vascular endothelial growth factor receptor, 54 intracellular domain cleavage by g-secretase, 54 GAPs. See GTPase-activating proteins nuclear trafficking, 58, 73–74 Gas6, TAM receptor binding, 371, 373, 377 structure, 409–410 Gastrointestinal stromal tumor, Kit role, 217 substrates, 411 Gefitinib, lung cancer management, 166 ubiquitination and endocytosis, 83–84 GEFs. See Guanine nucleotide exchange factors Insulin receptor Genetic screens, tyrosine phosphorylation, 24–25 activation, 151–152 GGA3, receptor tyrosine kinase sorting role, 104 Drosophila studies, 345–347 Glial-derived neurotrophic factor (GDNF), RET endocytosis, 80 binding, 278 history of study, 1, 3 Granzyme B, intracellular domain cleavage from insulin resistance defects, 418 receptor tyrosine kinases, 56 intracellular domain cleavage by g-secretase, 54 Grb2 kinase domain regulation, 152–153 insulin receptor signaling, 414 negative regulator recruitment, 155–157 MET signaling, 438 negative regulators receptor endocytosis role, 83 Grb10, 416 recruitment, 30–31, 37–38 Grb14, 416 RET signaling, 281 lipid phosphatases, 415–416 SH2 domain, 9, 33, 37 protein phosphatases, 414–415 SH3 domains, 9, 38 serine/threonine phosphorylation, 416–418 Sprouty binding, 141 suppressor of cytokine signaling, 416 Grb10 Trb3, 416 insulin action modulation, 416 prospects for study, 157–158 insulin receptor regulation, 156–157 recycling, 87 Grb14 signaling insulin action modulation, 416 3-phosphoinositide-dependent protein insulin receptor regulation, 155–157 kinase 1, 412–414 GTPase-activating proteins (GAPs) Akt, 412–413 ephrin receptor signaling, 308 Foxo1, 413 receptor tyrosine kinase spatial signal Grb2, 414 propagation, 143–144 mitogen-activated protein kinase, 414 Guanine nucleotide exchange factors (GEFs) mTORC1, 413 ephrin receptor signaling, 308 nitric oxide, 413 receptor tyrosine kinase spatial signal phosphatidylinositol 3-kinase, 411–412 propagation, 143–144 protein kinase C, 414 protein recruitment, 153–155 Ras, 414 H structure Heartless, Drosophila studies, 342–343 membrane topology, 150 Hematopoiesis, Kit role, 216 overview, 409–410 Heparan sulfate (HS), fibroblast growth factor subunits, 149–150 receptor binding, 250–252 three-dimensional structure, 150–151 Hepatocyte growth factor receptor. See MET substrates, 411 HER2. See ErbB2 Insulin receptor substrate 1 (IRS1) Herceptin, receptor tyrosine kinase inhibition, 18 insulin resistance defects, 418 Heregulins, ErbB receptor binding, 163 knockout mouse, 411 Hirschsprung’s disease, RET mutations, 282 PTB domain, 37 HS. See Heparan sulfate recruitment and activation of signaling Hypoxia, receptor tyrosine kinase endocytosis molecules, 10, 153–154 effects, 99–100 Insulin receptor substrate 2 (IRS2), recruitment, 154

473 Index

Insulin receptor substrate 3 (IRS3), mastocytosis, 217 tissue distribution, 411 melanoma, 217 Insulin receptor substrate 4 (IRS4), piebaldism, 218 tissue distribution, 411 down-regulation, 216 Insulin resistance functions gene defects fertility, 217 Akt, 420 hematopoiesis, 216 insulin receptor, 418 neurons, 217 insulin receptor substrate 1, 418 peristalsis, 217 phosphatidylinositol 3-kinase, 418 pigmentation, 216–217 PTEN, 419 ligand dimers, 8 hyperglycemia mechanisms, 421 phosphorylation sites, 9 lipotoxicity, 420 prospects for study, 218 mitochondrial dysfunction, 421–422 signaling, 215–216 obesity-associated inflammation, 421 stem cell factor activation, 215 prospects for study, 422 KLF2, 141–142 unfolded protein response, 422 Klotho, fibroblast growth factor receptor signaling, Internalization. See Endocytosis, receptor 252–253 tyrosine kinases Intracellular domain (ICD) caspase cleavage from receptor tyrosine kinases, 55 L g-secretase cleavage from receptor tyrosine kinases Leukemia, RET mutations, 460–461 colony-stimulating factor-1 receptor, 53–54 Ligand shedding. See also specific ligands and receptors Ephrin-B2 receptor, 53 ADAM proteases, 119–123 ErbB-4, 50–53 cancer dysregulation, 126–127 fibroblast growth factor receptor 3, 55 Drosophila studies, 116–118 insulin receptor, 54 ephrins, 126 insulin-like growth factor-1 receptor, 54 epidermal growth factor receptor ligands, 118–119 Met, 55 rhomboids, 123–125 overview, 49–51 lin-18, Wnt signaling, 330–332 protein tyrosine kinase 7, 55 LRIG1, 140–141 Ryk, 54–55 LRP1, ephrin receptor association, 314–315 Tie1, 54 Lrp4 vascular endothelial growth factor receptor, 54 Agrin binding, 265, 269–270 granzyme B cleavage from receptor myasthenia gravis autoantibodies, 271–272 tyrosine kinases, 56 neuromuscular synapse formation role, 265–268 prospects for study, 59 structure and function, 269–270 rhomboid-dependent fragments, 56 LRP5, Wnt ligands, 325–326 iRhoms. See Rhomboids LRP6 IRS1. See Insulin receptor substrate 1 ligand concentration effects on entry routes and IRS2. See Insulin receptor substrate 2 intracellular fate, 98–99 IRS3. See Insulin receptor substrate 3 Wnt ligands, 325–326 IRS4. See Insulin receptor substrate 4 Lung cancer epidermal growth factor receptor mutations and therapeutic targeting, 166, 168 J Kit role, 217–218 JAK, TAM receptor signaling, 371 RET mutations, 460 Lymphangiogenesis. See Angiogenesis Lymphedema, lymphangiogenesis defects, 375 K Kinome, human, 16 Kit M diseases MAPK. See Mitogen-activated protein kinase acute myeloid leukemia, 217 Mass spectrometry (MS) gastrointestinal stromal tumor, 217 kinase assays, 23–24 lung cancer, 217–218 phosphotyrosine proteomics, 22

474 Index

Mastocytosis, Kit role, 217 signaling, 270–271 Medullary thyroid carcinoma (MTC), structure RET mutation, 458–459 extracellular region, 268 Melanoma, Kit role, 217 intracellular region, 268–269 MEN2. See Multiple endocrine neoplasia type 2 MuSK. See Muscle-specific kinase Mer. See TAM receptors MvB. See Multivesicular body MET Myasthenia gravis (MG), autoantibodies, 271–272 activation ligand induction, 436 mutational activation, 439–441 N functional overview, 433–434 Nck history of study, 433–434 ephrin receptor signaling, 308 intracellular domain cleavage by g-secretase, 55 platelet-derived growth factor receptor binding, 210 knockout and transgenic mouse studies, 441–443 SH2/SH3 domains, 9 nuclear trafficking, 59 NEDD4, receptor endocytosis role, 83–84 prospects for study, 444–445 Neurotrophic receptor kinase (Nrk), Drosophila signaling function, 349 Akt, 437 Nitric oxide (NO), insulin receptor signaling, 413 Cbl, 439 NMDA receptor, ephrin receptor phosphorylation, Gab1, 436–437 312–313 Grb2, 438 NMR. See Nuclear magnetic resonance mitogen-activated protein kinase, 437–438 NO. See Nitric oxide phosphatidylinositol 3-kinase, 437–438 Noonan syndrome, Shp2 defects, 42–43 Ras, 437–438 Nrk. See Neurotrophic receptor kinase STAT3, 438 Nuclear magnetic resonance (NMR), phosphotyrosine termination, 438–439 protein structure, 22, 26 sorting proteins, 103–104 structure hepatocyte growth factor ligand, 434–435 O receptor, 434–436 Offtrack (Otk), Drosophila studies, 350–351 therapeutic targeting in cancer, 443–444 Otk. See Offtrack Metabolic syndrome. See Insulin resistance MG. See Myasthenia gravis Mig-6, 141 P Milestones, receptor tyrosine kinase studies, 2 p38 mitogen-activated protein kinase. See Mitogen- Mitogen-activated protein kinase (MAPK) activated protein kinase insulin receptor signaling, 414 Pancreatic cancer, RET mutations, 461 MET signaling, 437–438 Papillary thyroid carcinoma (PTC), RET defects receptor tyrosine kinase fusion partners of RET, 456 endocytosis induction, 99 oncogenes, 453 signaling cross-talk, 9–10, 134–137, 142–143 RET/PTC RET signaling, 280–281 formation mechanisms, 455 TAM receptor signaling, 371 oncogenic activation mechanisms, 455–456 MS. See Mass spectrometry; Multiple sclerosis oncogenic activity, 454–455 MTC. See Medullary thyroid carcinoma prevalence, 453–454 mTORC1, insulin receptor signaling, 413 PCP. See Planar cell polarity Multiple endocrine neoplasia type 2 (MEN2), PDGFR. See Platelet-derived growth factor receptor RET mutations, 457–458 PDK-1. See 3-Phosphoinositide-dependent protein Multiple sclerosis (MS), TAM receptor defects, 377 kinase 1 Multivesicular body (MVB), receptor tyrosine kinase PDZ domain, ephrin receptor signaling, 311 sorting, 85–87 Peristalsis, Kit role, 217 Muscle-specific kinase (MuSK) Phosphatidylinositol 3-kinase (PI3K) functional overview, 265–266, 272 Grb2 in signaling, 38 myasthenia gravis autoantibodies, 271–272 insulin receptor signaling, 411–412 neuromuscular synapse formation role, 266–268 insulin resistance defects, 418 prospects for study, 272–273 MET signaling, 437–438

475 Index

Phosphatidylinositol 3-kinase (PI3K) (Continued) insulin receptor signaling, 414 RET signaling, 280–281 receptor tyrosine kinase TAM receptor signaling, 371 endocytosis induction, 99 Phosphatidylserine, TAM receptor signaling role, sorting role, 104 371, 373 vascular endothelial growth factor receptor 3-Phosphoinositide-dependent protein kinase 1 signaling, 232–234 (PDK-1), insulin receptor signaling, Protein tyrosine kinase 7 (PRK7), intracellular domain 412–414 cleavage by g-secretase, 55 Phospholipase Cg (PLCg) PTB domain epidermal growth factor receptor association, 9 classification of proteins, 37 RET signaling, 280–281 diversity of proteins, 31–32 SH2-mediated assembly, 41–42 functions, 37 vascular endothelial growth factor receptor insulin receptor substrates, 153–154 signaling, 232–234 phosphotyrosine binding Phosphotyrosine (P.Tyr) binding modes, 36–37 abundance, 18–19 recognition, 30–31 chemical properties, 19 signaling in disease, 42 detection, 23–24 structure of binding domains, 36 PI3K. See Phosphatidylinositol 3-kinase recruitment of proteins by activated receptor Piebaldism, Kit role, 218 tyrosine kinases, 17 Pigmentation, Kit role, 216–217 PTC. See Papillary thyroid carcinoma PKA. See Protein kinase A PTEN PKC. See Protein kinase C insulin action modulation, 415 Planar cell polarity (PCP), Ror role, 330 insulin resistance defects, 419 Platelet-derived growth factor receptor (PDGFR) PTP1B, insulin receptor regulation, 155–157 activation, 209–210 P. Ty r . See Phosphotyrosine angiogenesis role, 388 Pvr, Drosophila studies, 354–356 dimerization, 5 disease processes atherosclerosis, 214 R fibrosis, 214 RA. See Rheumatoid arthritis therapeutic targeting, 214–215 Ragulator complex, 107 tumor cell overactivity, 213–214 RALT/Mig-6, receptor endocytosis role, 84 virus binding, 214 Rapsyn, 270–272 embryo development function, 211–212 Ras history of study, 2, 4, 17 ephrin receptor signaling, 310, 314 internalization and sorting, 211 insulin receptor signaling, 414 ligand concentration effects on entry routes MET signaling, 437–438 and intracellular fate, 97–98 receptor tyrosine kinase signaling cross-talk, 9–10 ligand shedding, 126 RET signaling, 280–281 ligands Reactive oxygen species (ROS), insulin resistance role, binding specificity, 208–209 421–422 dimers, 8 Recycling, receptor tyrosine kinases phosphorylation sites, 9 degradation versus recycling signals signaling receptor tyrosine kinase-based sorting activation of pathways, 210–211 signals, 103–104 modulation, 211 sorting proteins, 104–105 ubiquitination, 80 mechanisms, 87–88 wound healing role, 212–213 RET PLCg. See Phospholipase Cg activation, 451–452 Preeclampsis, sFlt-1 role, 232 breast cancer mutations, 461 Presenelin, substrate recognition, 51–52, 69 coreceptors, 278 PRK7. See Protein tyrosine kinase 7 Drosophila studies, 353 Pros1, TAM receptor binding, 371, 373, 377 evolution, 278–279 Protein kinase A (PKA), RET signaling, 281 functional overview, 452–453 Protein kinase C (PKC) gain-and loss-of-function mutations, 459–460

476 Index

inhibitors, 461 Doughnut, 352 kidney development role, 281–282 intracellular domain cleavage by g-secretase, 54–55 leukemia mutations, 460–461 nuclear signaling, 70 ligands, 278, 452 prospects for study, 332 lung cancer mutations, 460 Wnt signaling, 70, 330–332 medullary thyroid carcinoma mutation, 458–459 multiple endocrine neoplasia type 2 mutations, 457–458 S mutation and disease, 278 Sec61, nuclear trafficking of receptor nervous system development role tyrosine kinases, 57–58 enteric nervous system, 282 Sevenless, cell fate specification in eye motoneurons, 282 and testes, 340–341 ventral midbrain dopaminergic neurons, SH2 domain 282–283 Crk signaling complex assembly, 38 pancreatic cancer mutations, 461 diversity of proteins, 31–32 papillary thyroid carcinoma insulin receptor-interacting proteins, 154–156 fusion partners of RET, 456 kinase allosteric activation, 39–40 oncogenes, 453 kinase inhibition by intramolecular RET/PTC interactions, 38–39 formation mechanisms, 455 overview, 9 oncogenic activation mechanisms, 455–456 phospholipase Cg assembly mediation, 41–42 oncogenic activity, 454–455 phosphotyrosine binding prevalence, 453–454 canonical binding, 33–35 point mutations and oncogenesis, 459 noncanonical binding, 35 prospects for study, 283 recognition, 30–31, 33 signaling, 280–281 signaling in disease, 42–43 structure, 277–278, 451 prospects for study, 43 structure–function studies, 279–280 receptor tyrosine kinase adapter proteins, 9 therapeutic targeting, 461–462 recruitment of proteins by activated receptor tissue distribution, 453 tyrosine kinases, 17 RHBDL2, 215 Shp2 phosphatase regulation, 40–41 Rheumatoid arthritis (RA), TAM receptor signaling adaptor recruitment, 37–38 defects, 375, 377 STAT dimerization mediation, 31 Rho, ephrin receptor signaling, 308–310 tyrosine kinase target identification, 22–23 Rhomboids SH3 domain domain structure, 116–117 Crk signaling complex assembly, 38 Drosophila, 116–117, 125 overview, 9 mammals receptor tyrosine kinase adapter proteins, 9, 31 iRhoms, 123–125 tyrosine kinase target identification, 23 types, 125 Shc, platelet-derived growth factor receptor binding, 210 RIN1, receptor endocytosis role, 84 SHIP proteins, insulin action modulation, 416 RKIP, 140 SHP1, Kit regulation, 216 Ron, nuclear trafficking, 58–59 Shp2 Ror mutation in disease, 42–43 cancer role, 328 phosphatase regulation by SH2 domains, 40–41 developmental function SLE. See Systemic lupus erythematosus invertebrates and amphibians, 326, 349 SOCS. See Suppressor of cytokine signaling mammals, 327–328 Sorting. See Endosomal sorting, history of study, 326 receptor tyrosine kinases prospects for study, 332 Sprouty, 141 signaling, 328–330 STAM, endosomal sorting role, 85–86 ROS. See Reactive oxygen species STAT Ryk SH2 domain proteins in dimerization mediation, 31 Drosophila studies STAT3 in MET signaling, 438 Derailed, 351–352 TAM receptor signaling, 371 Derailed 2, 352–353 Stem cell factor receptor. See Kit

477 Index

Suppressor of cytokine signaling (SOCS), insulin V action modulation, 416 Vascular endothelial growth factor receptor (VEGFR) Systemic lupus erythematosus (SLE), TAM receptor angiogenesis role defects, 375, 377 development, 388–389, 391–392 lymphedema defects, 395 T tumor angiogenesis, 393–394 coreceptor-modulated sorting of ligand–receptor TACE. See ADAM17 complexes, 103 TAM receptors cross talk, 234 apoptotic cell clearance role, 373–374 endocytosis, 80, 99–101 autoimmune disease defects, 375–377 endoplasmic reticulum in signaling cancer role, 378–379 modulation, 108 innate immunity role, 374–376 functional overview knockout mice, 374–375 sFlt-1, 231–232 overview of types and functions, 369–370 VEGFR1, 229 prospects for study, 379 VEGFR2, 230 signaling, 371–373 VEGFR3, 230–231 structures, 370–371 gene therapy, 236 vasculature system regulation, 379 history of study, 227–228 virus entry factors, 377–378 inhibitor therapy Tetraspanins, ADAM shedding control, 122–123 antibody blockade, 398–399 Thyroid cancer. See Medullary thyroid carcinoma; ligand inhibitors, 397–398 Papillary thyroid carcinoma overview, 396 Tie1 tyrosine kinase inhibitors, 396–397 g intracellular domain cleavage by -secretase, 54 intracellular domain cleavage by g-secretase, 54 knockout mouse, 392 nuclear trafficking, 59 ligands, 391 overview, 227–229 Tie2 phylogenetic development, 234 functional overview, 287–288 signal transduction, 232–234 kinase domain structure and signaling, 291–292 structure, 229 knockout mouse, 392 therapeutic applications, 394–395 ligands, 391 therapeutic targeting, 234–236 ligands types and ligands, 389–390 angiopoietin recognition studies, 290–291 VEGFR2 nuclear function, 73 types, 288–289 VEGFR. See Vascular endothelial growth factor structure, 289–290 receptor Tie1 role in signaling, 292–293 v-Src, oncogenesis, 43 Tie-like receptor tyrosine kinase, Drosophila studies, 356 Torso, role in anterior/posterior patterning and metamorphosis, 339–340 W Trb3, insulin action modulation, 416 TrkA Wnt endosomal signaling, 105 Derailed mediation, 330–332, 351–352 endosomal sorting, 87 receptors, 325–326 nuclear localization in liver, 70–71 Ror mediation, 329–330 Tyro3. See TAM receptors Ryk activation, 70, 330–332 vascular endothelial growth factor receptor signaling cross talk, 234 U Unfolded protein response (UPR), insulin resistance role, 422 Z UPR. See Unfolded protein response Zap-70, SH2 domain, 33 Usp8, endosomal sorting role, 86 ZEB1, 141

478