Biomathematical and Biomechanical Modeling of the Circulatory and Ventilatory Systems Volume For further volumes: http://www.springer.com/series/10155 Marc Thiriet Signaling at the Cell Surface in the Circulatory and Ventilatory Systems Marc Thiriet Project-team INRIA-UPMC-CNRS REO Laboratoire Jacques-Louis Lions, CNRS UMR 7598 Université Pierre et Marie Curie Place Jussieu 75252 Paris Cedex 05 France ISSN 2193-1682 ISBN 978-1-4614-1990-7 e-ISBN 978-1-4614-1991-4 DOI 10.1007/978-1-4614-1991-4 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2011943886 Springer Science+Business Media, LLC 2012 All rights reserved This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Contents Introduction Signal Transduction 1.1 Main Signaling Features 1.1.1 Types of Cell Communications 1.1.2 Phases of Cell Communications 1.1.3 Main Signaling Mediators 1.1.4 Signaling Cascade 1.1.5 Features of Signaling Cascades 1.2 Signal Processing 1.2.1 Transducers 1.2.2 Molecule Translocation 1.2.3 Proteic Interactions – Interactomes 1.2.4 Lipidic Interactions 1.2.5 Protein Modifications 1.2.6 Reversible Oxidation of Kinases and Phosphatases 1.2.7 Receptor Endocytosis 1.2.8 Gene Expression 1.3 Signaling Triggered by Ligand-Bound Receptor 1.3.1 Signaling Initiation 1.3.2 Molecule Transformations and Multicomponent Complexes 1.3.3 Coupled Pathways 1.3.4 Feedback Loops 1.3.5 Cell Type Specificity 1.3.6 Signal Specificity 1.3.7 Pathway Complexity 1.3.8 Modeling and Simulation 1.4 MicroRNAs in Cell Signaling 1.5 Adenosine Triphosphate 1.5.1 ATP Messenger and Neurotransmitter 1.5.2 Basal and Stimulated ATP Release 11 12 12 13 14 14 15 26 26 26 27 33 33 58 59 59 60 61 63 64 65 68 68 70 73 77 80 80 80 V VI Contents 1.5.3 1.5.4 1.5.5 1.5.6 1.5.7 1.5.8 1.5.9 1.5.10 1.5.11 Cell Volume Control and Molecular Exchanges Cellular Processes for ATP Release Neuroregulator ATP ATP Release by Endothelial Cells ATP Release by Thrombocytes ATP Release by Leukocytes ATP Release by Erythrocytes Target Receptors of Extracellular ATP Extracellular Metabolism of Nucleotides 81 81 82 84 85 85 86 86 87 Ion Carriers 2.1 Connexins and Pannexins 2.1.1 Connexins 2.1.2 Pannexins 2.2 Ion Carriers 2.2.1 Ion Carriers in Cell Signaling 2.2.2 Types of Ion Carriers 2.2.3 Transmembrane Transporters 2.2.4 Ion Carrier Features 2.2.5 Ion Channels and Pumps 2.3 Superfamily of Transient Receptor Potential Channels 2.3.1 Classification of TRP Channels 2.3.2 Structure of TRP Channels 2.3.3 TRP Channel Activity 2.3.4 Families of Transient Receptor Potential Channels 2.3.5 TRP Channels in the Cardiovascular Apparatus 2.3.6 Cyclic Nucleotide-Gated Channels 2.4 Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels 2.4.1 Molecule Diversity 2.4.2 Cellular Distribution 2.5 Ligand-Gated Ion Channels 2.5.1 Superfamily of Cys-Loop Ligand-Gated Ion Channels 2.5.2 Nicotinic Acetylcholine Receptor Channel 2.5.3 γ-Aminobutyric Acid Receptor Channel 2.5.4 Glutamate Receptor Channels 2.5.5 Glycine Receptor Channels 2.5.6 Serotonin Receptor Channels 2.5.7 Ionotropic Nucleotide Receptors 2.5.8 Zinc-Activated Channel 2.6 Chanzymes 2.7 Ion Carriers and Regulation of H+ Concentration 89 89 89 90 91 91 91 92 93 95 109 109 111 111 116 134 136 137 137 138 138 139 140 141 142 149 149 150 152 153 153 Contents Main Sets of Ion Channels and Pumps 3.1 Introduction 3.1.1 Ion Channels 3.1.2 Ion Pumps 3.2 Calcium Carriers 3.2.1 Calcium Release-Activated Ca++ Channels 3.2.2 Calcium Channel-Induced Ca++ Release 3.2.3 Voltage-Gated Calcium Channels 3.2.4 Two-Pore Calcium Channels 3.2.5 Inositol Trisphosphate-Sensitive Calcium-Release Channels 3.2.6 Ryanodine-Sensitive Calcium-Release Channels 3.2.7 Sarco(endo)plasmic Reticulum Calcium ATPase 3.2.8 Plasma Membrane Calcium ATPase 3.2.9 Secretory Pathway Calcium ATPase 3.2.10 Sodium–Calcium Exchangers 3.2.11 Calcium Channel Expression during the Cell Cycle 3.3 Sodium Carriers 3.3.1 Epithelial Sodium Channel 3.3.2 Hydrogen-Gated Sodium Channels – Acid-Sensing Ion Channel 3.3.3 Sodium–Hydrogen Exchangers 3.3.4 Voltage-Insensitive, Non-Selective, Sodium Leak Channel 3.3.5 Voltage-Gated Sodium Channels 3.3.6 Sodium–Potassium Pump 3.3.7 Sodium Symporters 3.4 Potassium Carriers 3.4.1 Ligand-Gated Potassium Channels 3.4.2 Potassium Channel Structure and Groups 3.4.3 Gating Modes 3.4.4 Inwardly Rectifying Potassium Channels 3.4.5 Voltage-Gated KV Channels 3.4.6 Calcium-Gated Potassium Channels BK, IK, and SK 3.4.7 Sodium-Activated Potassium Channels 3.4.8 Hyperpolarization-Activated Cyclic Nucleotide-Gated Potassium Channels 3.4.9 Potassium Channels of the TWIK Subclass 3.5 Chloride Carriers 3.5.1 Voltage-Gated Chloride Channels 3.5.2 Chloride Channels of the Anoctamin Family 3.5.3 Bestrophins 3.5.4 Maxi and Tweety Homologs 3.5.5 Volume-Regulated Chloride Channels 3.5.6 Calcium-Activated Chloride (Pseudo)Channels 3.5.7 Chloride Intracellular (Pseudo)Channels 3.5.8 Nucleotide-Sensitive Chloride Channels VII 157 157 158 159 160 162 167 167 172 173 180 193 195 196 196 198 199 200 204 206 208 208 212 215 215 216 217 220 222 230 244 252 252 253 255 255 259 259 259 261 262 263 265 VIII Contents 3.5.9 Cystic Fibrosis Transmembrane Conductance Regulator 3.6 Proton Carriers 3.6.1 Voltage-Gated Proton Channels 3.6.2 Proton Pump 3.7 Other Types of ATPases 3.7.1 Copper-Transporting ATPases 3.7.2 Phospholipid-Translocating Mg++ ATPases 265 266 267 269 270 270 271 Transmembrane Compound Carriers 4.1 Superclass of Solute Carriers 4.2 Class of Solute Carrier Organic Anion Transporters (SLCO) 4.3 Amino Acid Transporters 4.3.1 Members of Solute Carrier Superclass 4.3.2 Cysteine and Cystine Transporters 4.4 Symporters or Secondary Active Transporters 4.4.1 Sodium–Taurocholate Cotransporter, A SLC10 Symporter 4.4.2 Monocarboxylate Transporters, SLC16 Members 4.5 Ion Transporters 4.5.1 Copper Exporters and Importers 4.5.2 Iron Transporters 4.5.3 Magnesium Transporters 4.6 Cation–Chloride Cotransporters 4.6.1 K+ –Cl− Cotransporters 4.6.2 Na+ –Cl− Cotransporters 4.6.3 Na+ –K+ –2Cl− Cotransporters 4.7 Ion-Coupled Solute Transporters 4.8 Neurotransmitter Transporters 4.8.1 Choline and Acetylcholine Transporters 4.8.2 Sodium- and Chloride-Dependent Neurotransmitter Transporters 4.8.3 Vesicular Monoamine Transporters 4.9 Adenine Nucleotide Transporters 4.10 Nucleoside Transporters 4.11 Nucleobase–Ascorbate Transporters 4.12 Fatty Acid-Binding Proteins 4.13 Retinoid-Binding Proteins 4.14 Flavonoid Transporter 4.15 Citrate and Succinate Transporters 4.16 Aquaporins 4.16.1 Aquaporin Family 4.16.2 Water-Selective Aquaporins 4.16.3 Aquaglyceroporins 4.16.4 Structural and Functional Features 4.16.5 Aquaporins in the Respiratory Epithelium 4.16.6 Aquaporins in the Nephron 273 274 274 276 276 280 280 281 281 283 283 285 285 286 286 286 288 290 290 290 291 298 299 299 301 301 301 303 304 305 305 305 307 308 308 309 Contents IX 4.17 Glucose Carriers 4.17.1 Sodium–Glucose Cotransporters – Active Transport 4.17.2 Glucose Transporters – Passive Transport 4.18 Superclass of ATP-Binding Cassette Transporters 4.18.1 Classification of ABC transporters 4.18.2 Structure of ABC Transporters 4.18.3 ABC Exporters and Importers 4.18.4 Full and Half ABC Transporters 4.18.5 Role of ABC Transporters 4.18.6 Class-A ABC Transporters 4.18.7 Class-B ABC Transporters (MDR–TAP) 4.18.8 Class-C ABC Transporters (MRP–CFTR) 4.18.9 Class-D of ABC Transporters (ALD) 4.18.10Class-E of ABC Transporters (OABP) 4.18.11Class-F ABC Transporters (GCN20) 4.18.12Class-G ABC Transporters (WHITE Class) 4.18.13Arsenite Transporters 4.19 Gas Transporters 311 311 311 315 315 318 318 319 319 320 323 326 329 330 331 332 333 333 Receptors of Cell–Matrix Mass Transfer 5.1 Endocytosis-Devoted Low-Density Lipoprotein Receptors 5.1.1 Low-Density Lipoprotein Receptor 5.1.2 Low-Density Lipoprotein Receptor-Related Proteins 5.1.3 ApoER2 (LRP8) and VLDLR 5.2 Scavenger Receptors 5.2.1 Class-A Scavenger Receptors 5.2.2 Class-B Scavenger Receptors 5.2.3 Other Types of Scavenger Receptors 335 335 336 339 349 350 352 354 358 Receptors 6.1 Introduction 6.1.1 Catalytic and Non-Catalytic Receptors 6.1.2 Cell-Surface and Intracellular Receptors 6.1.3 Catalytic Receptor-Initiated Signaling 6.1.4 Organization of Receptors at the Plasma Membrane 6.1.5 Chemosensors 6.2 Plasmalemmal Receptors 6.2.1 Main Families of Catalytic Plasmalemmal Receptors 6.2.2 Ionotropic Receptors – Ligand-Gated Ion Channels 6.3 Intracellular or Nuclear Receptors 6.3.1 Ligands 6.3.2 Structure and Function 6.3.3 Classification 6.3.4 Transcriptional Regulation 6.3.5 Intracellular Hormone Receptors 361 362 362 363 363 364 364 366 366 372 372 372 373 375 377 386 968 Index allergen 302 allostery 28 alveolar macrophage 340, 353 alveolus 267, 322 ALX adaptor 789 AMP 85 amphetamine 585 amphiregulin 605 AMPK 42, 419, 492 amylin 513 amyloid precursor protein 340, 347 anandamide 116, 129, 132 anaphylatoxin 519 androgen receptor 388 aneurysm 506 angiogenesis 79, 85, 283, 398, 432, 478, 480, 509, 529, 548, 550, 553, 563, 566, 573, 582, 619, 621, 626, 636, 653, 658, 660, 693, 700, 703, 715, 720, 739, 746, 769 angiopoietin 660, 693, 715 angiotensin 131, 134, 185, 243, 287, 344, 413, 420, 504, 530, 618, 619 angiotensin-converting enzyme 39, 506, 511, 513 angiotensin receptor 238, 464, 487, 504 ankyrin 158, 177, 179, 211, 229 annexin 418, 546 anoctamin 259 antiporter 91 aortic body 365 APC Ub ligase 737 apelin 419, 508 apelin receptor 419, 508 apolipoprotein 321, 332, 352, 405, 672, 674 apolipoprotein-E receptor 349 apoptosis 113, 774 APS adaptor 790 aquaporin 305, 328, 587 arachidonic acid 82, 129, 132, 133, 234, 516, 517, 524, 544 ARF GTPase 404 arginine 414 Argosome 736 arrestin 131, 459, 462, 490, 577, 578, 612, 707, 726, 740 arrhythmogenic right ventricular dysplasia 667 artemin 651 arterial tortuosity syndrome 315 asbestos 619 asthma 762 atherosclerosis 332, 341, 352, 359, 406, 439, 516, 645 ATP 80, 81, 85, 87, 89, 123, 133, 150, 159, 167, 173, 176, 177, 179, 183, 187, 189, 193, 227, 228, 259–262, 266, 289, 299, 308, 379, 409, 483, 485, 487, 490, 491, 799 ATP synthase 269 ATP anion 81, 260 autoregulation 480 autotaxin 550 axin 732 Axl (RTK) 596, 642, 803 B β-adrenergic receptor51, 461, 466, 479, 481, 493, 512 B-cell receptor 58, 783 BACE protease 57 Bardet-Biedl syndrome protein 742 baroreceptor 200 baroreflex 475, 496 basal cell 326 BCAR/CAS docker 417, 645 BCL2 protein 178, 530 bestrophin 259 Bezold-Jarisch reflex 117 biased signaling 500 bicarbonate 153, 266 biglycan 625, 736 bile acid 392, 402, 510 bilitranslocase 303 biomarker 259 birth 530 bistability 676 BK channel 181, 220, 226, 244 BLnk adaptor 790 blood–brain barrier 312, 323, 325, 431, 541, 543, 765 blood pressure 202 blood volume 202 BMP 345, 668, 674, 713 bombesin 510 Bowditch/Treppe effect 189 bradykinin .415, 510 bradykinin receptor 510 Index brain 90, 121, 198, 213, 282, 286, 315, 322, 328, 336, 419 BrCa1 Ub ligase 50 breathing frequency 365, 576 bronchoconstriction 452, 472, 473, 544 bronchodilation 452, 499 brush cell 207, 258, 323, 365 C C-reactive protein .765 C/EBP factor 396, 397 C1qTNFSF 148 Ca++ -induced Ca++ release 180, 185, 186 Ca++ 2-pore channel 172 CaV channel 132, 164, 167, 169, 240, 248, 308, 409, 452, 487, 523, 535, 543, 560, 745 cadherin 492, 645, 697 cADPR 161, 185 calcitonin 513 calcitonin gene-related peptide 83, 117, 513 calcium 32, 42, 65–67, 80, 81, 83, 89–91, 111, 113, 116, 119, 121, 123, 126, 127, 130–133, 147, 157, 160, 173, 179, 244, 287, 308, 341, 343, 365, 414, 491, 496, 514, 524, 532, 720 calcium-sensing receptor 514 calcium blip 180 calcium oscillation 179 calcium puff 173, 175, 180 calcium spark 175, 181, 187, 248 calcium transient 126 calcium wave 180, 181 calmodulin 102, 119, 171, 178, 183, 250, 251, 467, 582 calmodulin-dependent kinase 35, 80, 144, 171, 172, 178, 183, 184, 189, 199, 226, 233, 237, 240, 501, 507, 681, 747 calpain 42, 178 calreticulin 340, 341 calsequestrin 189 Cam2K 493 cAMP 16, 32, 80, 133, 266, 308, 326, 388, 411, 490, 497, 543 cancer 530, 717 cannabinoid receptor 116, 515 carbonic anhydrase 153, 268 carbon dioxide 253, 333, 365 carbon monoxide 202, 247, 399 969 cardiac frequency 365, 521 cardiomyocyte 39, 51, 91, 135, 161, 167, 171, 174, 175, 181, 183, 196, 197, 206, 208, 210, 213, 214, 229, 237, 242, 249, 252, 260, 261, 266, 284, 293, 308, 313, 389, 409, 412, 419, 463, 464, 471, 480, 492, 499, 506, 507, 509, 515, 527, 530, 532, 563, 565, 567, 582, 602, 612, 619, 709, 744, 752, 790 cardiomyopathy 284, 481 cardiotonic steroid 214 cardiotrophin 767 carotid body 201, 247, 365 CARP2 (RFFL1) Ub ligase 782 casein kinase 127, 251, 388, 473, 646, 653, 720, 724, 732, 740 caspase 178, 627, 775, 781, 797 catenin 346, 696, 697, 728, 730 cathepsin 420, 568 caveola 214, 355, 356, 515, 612 caveolin 39, 49, 117, 176, 201, 229, 244, 265, 313, 389, 572, 614, 633, 666 CBLb adaptor 790 CBL Ub ligase 601, 603, 607, 630, 633, 639, 788, 805 CBP (HAT) 379, 381 CCPg adaptor 790 CD36 537 CDC25 phosphatase 41 cellulin 605 cell cycle 41, 239, 667, 749 cell migration 293, 319, 341, 342, 434, 630 cell polarity 637 central nervous system 140, 291, 419, 474, 522, 746 cerebellin 148 cerebrospinal fluid 365, 578 ceruloplasmin 284 CE transfer protein 350, 406 CFTR channel 81, 96, 155, 258, 262, 265, 319, 326, 498, 552 cGMP 17, 133 chemerin 420 chemerin receptor 420 chemokine 341, 359 chemokine receptor 517 chemotaxis 420, 518–520, 545, 584 Chibby 736 970 Index chloride 81, 85, 88, 95, 139, 141, 149, 157 cholecystokinin 520 cholesterol 237, 321, 350, 352, 392, 393, 399, 402, 403, 537 cholesterol ester transfer protein 402 choline 290 choline transporter 290 chondroitin sulfate proteoglycan 691, 698 choriogonadotropin 539 chromogranin 178 chylomicron 350, 403 chymase 420 chymotrypsin 568 cIAP Ub ligase 798 ciliary beat frequency 132, 133, 365, 634 ciliary neurotrophic factor 767 ciliated cell 326 circadian rhythm 401, 408, 542, 579 cis-acting factor 59 Cl− –H+ antiporter 255 Cl− –H+ exchanger 155, 255, 258 Cl− –HCO− exchanger 155, 265, 268, 327, 328 Clara cell 400, 534 clathrin 49, 614 clathrin-coated pit 285, 343, 464, 611 claudin 305 ClCa channel 181, 262, 265, 327, 487 ClC channel 81, 156, 255 ClIC channel 263 ClNS channel 82, 265 CNG channel 136, 216, 252 coagulation factor 420 cofilin 471 collagen 354, 643 collectin 353 complement 366, 519 connexin 89 connexon 89 contactin 691, 696 copper 283 copper ATPase 270, 283 copper transporter 283 cortactin 235 corticosterone 402 corticotropin-releasing hormone 521 cortisol 390 CRAC channel 162 creatine 414 creatine kinase 415 CREB factor 16, 168, 192, 198, 384 CRK adaptor 349, 626 crosstalk 40, 71, 79, 389, 456, 458, 503, 513 Cryptic 605, 665, 671 CSF2 332 CSF3 564 CSF receptor 640 CTDSP/SCP phosphatase 681 cubilin 344 cullin Ub ligase .737 cyclin-dependent kinase 178, 460, 641, 724, 763 cyclooxygenase132, 390, 515, 565, 567, 747 cystic fibrosis .88 cytochrome-C oxidase 283 cytochrome C 178 cytochrome P450 372, 402 cytokinesis 41 cytokine receptor 370 cytotoxic T cell 324 D Dab adaptor 339, 343, 349, 665, 672 DAPK kinase 147 DDR kinase 642 decorin 423, 625 Deltex Ub ligase 707 demethylase 43 dendritic cell 123, 280, 496, 641, 800 dermatan sulfate 625 DGK kinase 616 diabetes 799 diacylglycerol 110, 120, 244, 464, 505, 567 Dickkopf 739 diffusion 268 Disheveled 465, 646, 728, 730, 736, 741 Dispatched 719, 720 distal-less homeobox (DLx) 564 divalent metal transporter 285 DLg adaptor 144, 145, 223, 227, 239, 240, 343, 498, 576 DM2 Ub ligase 463 DOCK GEF 417 DOK adaptor 639, 646, 651, 660, 665, 789, 805 dopamine 84, 141, 225, 296, 310, 522, 578 dopamine receptor 265, 522 dynamin 719 Index dynein 674, 685 dynorphin 509, 524, 559 dystroglycan 36 dystrophin 196 E E2F factor 38, 683 EAAT transporter 292 ecto-5 -nucleotidase 17, 87, 474 ecto-alkaline phosphatase 87 ectonucleotidase 87 ectoprotein kinase 485 EET 90, 132, 255 EGF-like domain-containing protein 619 EGFR pathway substrate 607 EGF receptor 249, 381, 417, 507, 532, 602, 711 eicosanoid 129, 301 elastase 201, 420 electrolyte 93 embryo/fetus 175 ENaC channel 200, 226, 262, 265, 287, 327 endocannabinoid 129, 225, 515 endocytosis 630 endoglin 665, 669, 672, 678 endomorphin 225, 560 endophilin 498 endoplasmic reticulum 113 endoplasmic reticulum stress .195 endorphin 559 endosome 21, 59, 125, 258, 356, 629 endothelin134, 175, 185, 243, 325, 506, 526, 619 endothelin receptor 526 endothelium 45, 79, 84, 131, 132, 206, 230, 249, 262, 266, 303, 312, 353, 356, 357, 389, 397, 399, 410, 419, 473, 478, 490, 492, 507, 509, 527, 528, 541, 564, 580, 582, 628, 637, 658, 672, 678, 695, 697, 708, 709, 739, 746, 752, 753 ENDPK kinase 87, 88 enkephalin 509, 524, 559 ENPP ectonucleotidase 16, 87 ENTPD ectonucleotidase 86, 87, 474, 490 EpCAM 750 ephrin 653, 713 EPH receptor 593, 653 epican (CD44) 627 971 epidermal growth factor 73, 248, 389, 602, 724 epigen 605 epiregulin 605, 620 epithelial–mesenchymal transition 626 epithelium 206 epsin 607 ERK 23, 72, 81, 124, 201, 202, 214, 273, 286, 297, 341, 358, 389, 390, 399, 413, 417, 419, 421, 422, 439, 462, 487, 496, 501, 503, 506, 507, 510, 518, 522, 526, 527, 532, 533, 545, 548, 552, 561, 572, 574, 578, 579, 581, 588, 601, 606, 609, 612, 616, 619, 628, 630, 635, 645, 661, 667, 680, 685, 771, 773, 794 erythrocyte 81, 85, 86, 90, 216, 249, 266, 320, 580 ESCRT 59, 604, 615 estrogen 503, 531, 612, 696 estrogen-related receptor 392 estrogen GPCR 531, 540 excitatory postsynaptic potential 142, 145 exercise .490 exporter 91 ezrin–radixin–moesin 206, 265, 628 F farnesoid X receptor 392 fatty acid 301, 330, 398, 532 fatty acid-binding protein 301 fatty acid transport protein 637 Fc receptor 784 feedback 19, 21, 25, 32, 65, 71, 119, 132, 151, 166, 170, 171, 179, 186, 192, 245, 260, 263, 289, 349, 385, 393, 397, 399, 413, 416, 421, 441, 467, 491, 499, 509, 555, 598, 602, 607, 608, 613, 628, 644, 656, 679, 680, 707, 711–713, 719, 725 feedforward 162, 608 ferritin 285 FGF receptor 621, 771 fibrin 415 fibrinogen 491 fibroblast 206, 410, 506, 507, 570 fibroblast growth factor 249, 410, 691 fibronectin 738 fibrosis 645, 745 972 Index filamin 666 flavonoid 303 FLK2 (CD135) 640 flotillin 633 foam cell 332, 336, 358 focal adhesion 505, 739 focal adhesion kinase 381, 504, 645, 650, 657, 699, 789 follicle-stimulating hormone 539 Fos factor 181, 388, 516, 522 FoxC factor 715 FoxG factor 718 FoxH factor 666, 682 FoxO factor 661 Frizzled 346, 465, 535, 728 functional hyperemia 539 functional selectivity 500 furin 201, 339, 705 Fyn kinase 178, 349, 358, 633, 640 G GABA 84, 141, 225, 291 GABAA channel 141 GABAB receptor 226, 535 GAB adaptor 527, 617, 618, 626, 699, 788 GAds/GRAP2 adaptor 788 galanin 536 galanin-like peptide 536 ganglioside 601, 604 gap junction 90 gastrin 520 gastrin-releasing peptide 510 gas transporter 333 GATA factor 709 GDF 668 GDNF 650 gelsolin 549 general transcription factor GTF2 378, 392, 682 ghrelin 537 ghrelin receptor 399, 537 girdin 620 GIRK channel 216, 223, 410 glial cell 260 Gli factor 722 glucagon 503, 537 glucagon-like peptide 537 glucagon receptor 537 glucocorticoid 202, 237, 322, 402, 521 glucocorticoid receptor 145, 390 glucose 358, 522 glucose transporter 313, 398, 420, 630, 633 glutamate 84, 142, 414, 521, 538 glutamate–aspartate transporter 292 glutamate channel 142, 521, 747 glutamate receptor 538 glutathione 46 GLUT enhancer factor (GEF) 313 glycan 38 glycerol 308 glycine channel 149 glycogen synthase kinase206, 543, 667, 681, 724, 732 glycoprotein hormone receptor 539 glycosaminoglycan 47 glycosylation 38, 139, 150, 260 glypican 39 goblet cell 488 Golgi body 258, 283 gonadotropin-releasing hormone 540 GPCR 463 GPCR kinase 459, 473, 490, 578 GPCR phosphatase 460 GPI anchor 39 GRB adaptor 32, 40, 507, 526, 603, 631, 651, 788, 789 Gregg’s phenomenon 528 Groucho factor 743 growth factor 366, 601, 747 growth hormone-releasing hormone399, 537 gut flora 532 G protein 61 G protein-coupled receptor 366 H H+ –K+ ATPase 269, 328 H+ ATPase 254, 258, 268, 269, 298, 328, 413, 742 HV channel 106, 267 HBEGF 248 HCK kinase 763 HCN channel 137, 409, 452, 543 HCO− transporter 153, 254 HDL 332, 350, 352, 405 Head activator 347 heart 117, 121, 130, 282, 286, 293, 315, 322, 328, 336, 419, 527, 589, 649, 674, 698, 780 Index heart failure 240 heat-gated ion channel 112, 123, 124, 128, 130 heat shock protein 202, 387, 796, 799 HECW Ub ligase 737 Hedgehog 344, 464, 624, 709, 718 helper T cell 151 heme 202, 247 heme oxygenase 201, 202, 247, 399 heparan sulfate proteoglycan 39, 64, 340, 341, 344, 594, 623, 625, 636, 657, 688, 736, 739 heparin 341, 625, 736 hepatocyte 321, 328, 332, 393 hepatocyte growth factor 762 hepcidin 675 hepsin 624 HER receptor 503, 592, 593, 610 HES factor 708 HETE 129, 171, 398 HETEE 129 HGF activator 625 HGF receptor 624, 803 histamine .410, 541 histamine receptor 541 histone deacetylase 604, 613 HODE 398 Homer scaffold 179, 185, 192, 539 hormone 106, 215, 362, 366, 576 hormone response element 387 HPETE 129 HPETEE 129 HRS (ZFYVE8) 604, 607 HRT factor 708, 715 HUNK kinase 616 HUWE1 (ArfBP1) Ub ligase 401 hydrogen 90, 147, 153, 173 hydrogen ion control 94, 207, 412 hydrogen peroxide 411 hydrogen sulfide 230 hydronium ion 204, 266 hydroxylation 42 hypertension 135, 183, 214, 565 hypertrophy 617, 619 hypothalamus 509, 586 hypoxia 90, 167, 202, 230, 480, 567, 748 hypoxia-inducible factor 43, 747 973 I iKACh current 216 IDL 350 IDOL Ub ligase 337, 394 IGF2R receptor 416 IGF receptor 632 IK channel 249 imidazoline receptor 414 immunoglobulin 366 importer 91 infarction 532 inflammasome 797, 799 inflammation 399, 765 inhibin 668 initiation factor 331 inositol trisphosphate 67, 161, 172, 173, 244, 496, 567 inotropy 493 InsRR receptor 632 insulation 72 insulin 130, 206, 308, 312, 313, 321, 389, 415, 422, 473, 496, 500, 503, 521, 534, 593, 653, 695, 697, 739 insulin-like growth factor130, 286, 389, 724, 745 insulin-like peptide 573 insulin receptor 40, 423, 631 insulin receptor substrate 618, 632, 739 integrin 14, 64, 224, 261, 262, 265, 297, 358, 362, 417, 517, 627, 643, 645, 689, 738, 788 intercalated disc 206 interferon 330 interferon regulatory factor 797 interleukin 90, 297, 332, 747, 799 intermediate filament .613 intimal hyperplasia 134, 249 intracellular hormone receptor 363 intramembrane-cleaving protease 57 inversin 742 ion carrier 66 ion pump 108 IP3 receptor 214, 539 IQGAP 68 IRAK (pseudo)kinase 758, 793 iron 285 ischemic preconditioning 411, 480 Itch Ub ligase 131, 607, 616 ITK kinase 788 974 Index J Jade Ub ligase 748 JAMM metalloprotease 52 Janus kinase 421, 436, 504, 507, 563, 658, 694, 763, 803 JNK 125, 358, 436, 501, 508, 572, 581, 588, 616, 628, 635, 645, 656, 671, 674, 681, 730, 739–741, 747, 777, 794, 798 junctin 190 junctophilin 191 Jun factor 388, 516 K K+ –H+ exchanging ATPase 155 K1P channel 217 K2P channel 217, 218, 253 KATP channel 227, 329, 411, 415 KCa (BK) channel 478, 539 KCa (SK) channel 543 KCa channel 116, 132, 216, 220, 244 KIR channel 158, 222, 260, 318, 319, 327, 329, 409, 452, 478, 487, 516, 535, 539, 556, 560 KNa channel 220, 252 KV channel39, 219, 230, 327, 487, 543, 690, 695 kallidin 510 kallikrein 512 KCC cotransporter 262 kidney 54, 81, 92, 108, 111, 120, 123, 130, 131, 164, 202, 207, 255, 282, 286, 288, 290, 293, 299, 302, 305, 309, 311, 314, 315, 322, 328, 336, 412, 419, 522, 524, 589, 596, 643, 653, 671, 674, 698, 780 kinesin 721, 726 kinin 510 kininogen 510 kisspeptin 543 Klotho 622, 750 Kremen receptor 739 L lamellipodium 635 larynx 262 latrophilin GPCR 544 LAT adaptor 788 LcK kinase 694, 772, 789 LCP2 adaptor 788 LDL 350 LDLR-related protein 339, 416, 706, 728 LDLRAP adaptor 339 LDLR receptor 335, 336, 355, 407, 416, 728 lecithin–cholesterol acyltransferase 350, 406 lectin 353, 359, 422, 643, 800 leptin 421, 521, 534, 555 leptin receptor 421 leucyl–cystinyl aminopeptidase 312 leukemia inhibitory factor 767 leukocyte 106, 420, 491, 619, 755 leukotriene 129, 398, 544, 547 leukotriene receptor 544 LGR (GPCR) 739 LIMK kinase 471, 685 lipocalin 302 lipoprotein 366 lipoprotein lipase 350 lipoxin 544 lipoxygenase 129, 341, 545 liprin 688, 695, 696, 699 liver 121, 282, 299, 302, 314, 315, 328, 329, 336, 343, 419, 420, 527 liver kinase-B 493 liver X receptor 321, 323, 332, 393 long-QT syndrome 243 long-term potentiation .143 LPA receptor 551 LTK kinase 645 lung 107, 116, 117, 121, 164, 174, 176, 198, 213, 286, 299, 302, 305, 311, 314, 315, 320–322, 336, 353, 400, 419, 420, 527, 558, 572, 589, 596, 643, 645, 653, 671, 674, 688, 695, 697, 698, 718, 720, 762, 780, 781, 792 luteinizing hormone .539 lymphangiogenesis 553, 636, 638, 658 lymphatic 661 lymphocyte 108, 162, 172, 236, 249, 260, 280, 357, 487, 534, 580, 583, 641, 777, 787 Lyn kinase 131, 358, 616, 786 lysophosphatidic acid 398, 410, 465, 548, 550 lysophospholipid 548 lysosomal protein 356 lysosome 113, 125, 259, 356 Index M macrophage 280, 283, 321–323, 332, 350, 397, 399, 537, 564, 640, 644, 739, 747, 787, 802 magnesium 111, 133, 134, 147, 152, 153, 182, 183, 187, 251, 261, 271, 285, 287, 586 maltose transporter 318 manganese 196 mannose 6-phosphate receptor 412, 416 MAPK 19, 29, 30, 35, 68, 69, 73, 264, 293, 388, 460, 487, 492, 496, 504, 510, 527, 543, 564, 602, 656, 681, 724, 758, 763, 797 mastocyte 123, 176, 421, 454, 553, 584, 625, 639 MATK kinase 639 matriptase 624 Maxi anion channel 82, 259 mechanogated channel 107 mechanosensitive channel 107, 110, 119, 134, 156 mechanosome 12 mechanotransduction 86, 201, 308, 435, 454, 462, 659 Mediator complex 381 melanin-concentrating hormone 554 melanocortin receptor 554 melanocyte-stimulating hormone 554, 555 melatonin 556 membrane raft 39, 63, 332, 633 Mer (RTK) 596, 616, 642, 803 mesenchymal–epithelial transition 634 metallothionein 284 metastasis 262, 626 methylation 43 methyltransferase 43 Mg++ ATPase 271 Mg++ transporter 285 Mib Ub ligase 706 Mical 752 microphthalmia transcription factor (MiTF) 259 microRNA 21, 77, 321, 338, 395, 397, 499, 607, 609, 737 microtubule 211, 666 microtubule-associated protein 132 microvillus 265 midkine 691 975 mineralocorticoid receptor 145, 391 MIST adaptor 790 mitochondrial Ca++ uptake protein 162 mitochondrion 162, 198, 262, 283, 299, 315, 384 mitoferrin 285 mitofusin 710 mitogen- and stress-activated kinase 792 mitosignalosome 797 MJD deubiquitinase 52 MMP 57, 415, 553, 565, 570, 622, 628, 643–645, 769 monocarboxylate transporter 155, 281 monocyte 564 motilin 556 mRNA 59 mucin 488 mucociliary clearance 203, 262, 488 mucus 203, 263 multidrug resistance transporter 323 multivesicular body 61, 735 MuSK kinase 471, 646 MyB transcription factor 196, 199 MycBP2 Ub ligase 401 MyC transcription factor 264, 667, 682, 749 MyD88 adaptor 757, 792, 793 myocardin 390 myocardium 578 myocyte enhancer factor (MEF) 313 myogenic differentiation factor (MyoD) 683 myogenic response 134 myosin 313, 567 myosin light-chain kinase 494 myristoylation 45, 247, 444 myristoyltransferase 45 N Na+ –Ca++ –K+ exchanger 197 Na+ –Ca++ –Li+ exchanger 197 Na+ –Ca++ exchanger 135, 158, 166, 175, 186, 195, 196, 213, 420, 509, 526, 530 Na+ –Cl− cotransporter 92 Na+ –H+ antiporter 155 Na+ –H+ exchanger 153, 155, 206, 254, 268, 328, 343, 420, 499, 507, 509, 523, 524, 526, 530, 552, 562, 734 Na+ –HCO− symporter 155, 262 Na+ –K+ ATPase 158, 197, 200, 212, 226, 269, 292, 296, 523 976 Index NaV channel 39, 158, 208, 561, 693 NAADP 161, 172 NAADP receptor 172 NAD+ 172 NADPH oxidase 185, 268, 303, 307, 505, 635, 779 natriuretic peptide 17, 310, 407, 506, 507 natriuretic peptide receptor 407, 409, 556 NCK adaptor 381, 788 NCoA coactivator 379 NCoR corepressor 377 NDPK kinase 88 neddylation 56, 607 NEDD Ub ligase 202, 235, 261, 288, 607, 616 nephron 199, 202, 207, 226, 253, 286, 288, 291, 343 nerve growth factor 73 nervous system 527 nestin 613 neuralized Ub ligase 706 neuregulin 610, 613 neurite growth-promoting factor 691 neurogenic differentiation factor (NeuroD) 389 neurokinin 584 neuromedin B 510 neuromedin C 510 neuromedin N 558 neuromedin receptor 556 neuromedin S 557 neuromedin U 556 neuromuscular junction 82, 471, 646 neuron 213, 260, 422 neuropeptide B 557 neuropeptide EI 554 neuropeptide FF 543 neuropeptide GE 554 neuropeptide K 584 neuropeptide S 557 neuropeptide W 557 neuropeptide Y 422, 554, 556, 557 neurophysin 588 neuropilin 636, 751 neuroregulin 602, 713 neurotensin 347, 369, 524, 525, 558 neurotransmitter 106, 215, 225, 362, 366, 576 neurotrophin 646 neurotrophin RTK 646 neurturin 651 neutrophil 85, 283, 357, 433, 487, 546, 564 nexin 569, 674 NFκB 25, 45, 50, 341, 387, 398, 464, 465, 487, 628, 717, 736, 758, 773, 792, 797, 805 NFκB-inducing kinase 798 NFAT factor 199, 487, 530, 787, 805 NHERF 562 nicotine 140, 192 nicotinic acid 559 Niemann-Pick type-C protein 403 nitric oxide 17, 45, 83, 84, 132, 133, 178, 183, 184, 254, 305, 310, 333, 356, 390, 407, 411, 414, 473, 490, 491, 506, 512, 526, 598 nitric oxide synthase 45, 124, 183, 196, 266, 303, 325, 390, 399, 487, 506, 507, 530, 661 nitrosylation 45, 487 NKCC cotransporter 641 NKx2-5 factor 400 NMDA receptor 226 nociceptin 560 NOD-like receptor 796 Nodal 665 nodal cell 261, 409 non-receptor Tyr kinase 457 noradrenaline 82, 83, 170, 251, 296, 500 nose 262, 424 Notch 619, 623, 703, 720, 727 Notum pectinacetylesterase 39 NRF factor 709 nuclear estrogen receptor .24, 388 nuclear respiratory factor (NRF1) 384 nucleobinding (calnuc) 345, 348 nucleoside 474, 482 nucleotide 474, 482 O obesity 421 occludin 306 octopamine 585 omentin 422 oncostatin 767 opioid 559 Orai Ca++ channel 163 ORCC Cl− channel 265, 327 Index orexin 562 osmoreceptor 131 osmotic pressure 81, 107 osteoclast 802 osteoprotegerin 780 OTU deubiquitinase 52 oxidative stress 42, 56, 315, 353, 741 oxygen 247, 253, 333, 365 oxysterol 726 oxytocin 83, 586, 587 P P-type ATPase 160 P1 receptor 482 P21-activated kinase 381, 471, 609 P2X channel 80, 82, 90, 150, 260, 482 P2Y GPCR 80, 133, 260, 262, 482 P300 (HAT) 379, 381 P38MAPK 358, 419, 460, 501, 508, 516, 561, 581, 588, 606, 614, 628, 641, 671, 685, 773, 777, 794, 798 P53 transcription factor 33, 38, 41, 43, 44, 264, 699 P70 ribosomal S6 kinase (S6K) 419, 685 pacemaker 101, 137 palmitoylation 46, 233, 389, 444 pannexin 90, 487 parasympathetic 83, 650 parathyroid hormone 562 parathyroid hormone-related peptide 562 Patched 719, 725 paxillin 650, 657, 699, 789 PDGF receptor 417, 634 PDK1 kinase 633 Peli1 Ub ligase 794 pepducin 518 peptidase 339 peptidase-activated receptor 568 peptide YY 534 pericyte 658 peripheral nervous system 140 perivascular nerve 85 peroxisome 329, 330, 384 persephin 651 PGC factor 382 pH 204–206, 247, 253, 275, 281, 294, 300, 308, 328, 365, 439 phagocytosis .268, 804 phosphacan 700 977 phosphatidic acid 505, 550 phosphodiesterase 16, 535 phosphoinositide 113, 234 phospholamban .194 phospholipase A 132, 133, 505, 543, 550, 578 phospholipase C91, 113, 115–117, 125, 153, 162, 176, 226, 229, 244, 262, 409, 420, 475, 480, 486, 493, 505, 509, 511, 523, 543, 556, 572, 578, 598, 623, 626, 637, 788, 789 phospholipase D 33, 505, 578, 581 phospholipid 548 phosphorylation 20, 21, 31, 34, 150 PI3K202, 214, 341, 419, 460, 527, 532, 579, 598, 612, 615, 626, 633, 637, 656, 763, 789 PIAS SUMo ligase 765 Piezo (Fam38) 107 pituitary ACase-activating peptide 588 PKMyt kinase 41 plasmerosome 117, 164, 213, 214 plasmin 201, 415, 420, 624 plasminogen 415 platelet 178, 249, 265, 297, 320, 354, 357, 453, 491, 553, 642, 643, 803 platelet-activating factor 563 platelet-derived growth factor 410, 746 pleiotrophin 645, 691 plexin 628, 650, 751, 752 PLuNC 201 PMCA pump 186, 195 pneumocyte 322, 343, 344, 400 Polo-like kinase 749 polyADP ribosylglycosidase 41 polyADP ribosylpolymerase 41 polyadpribosylation 41 Polycomb chromatin repressor 779 polycystin 125, 434 polysialyltransferase 39 pore 91 potassium 81, 157 PP1 40, 172, 177, 184, 225, 233, 246, 527, 609, 672 PP2 44, 172, 177, 225, 251, 259, 410, 461, 512, 609, 672, 681, 724, 737 PP3 196, 233, 237, 410, 530, 564, 787 PPAR factor 301, 323, 352, 395, 419 PPM1 264, 410, 681 978 Index pre-Bötzinger complex 576 pregnancy 512 prenylation 46, 444 presenilin 611, 750 primary cilium 126, 435, 447, 720, 742 prion 340 prokineticin 563 prokineticin receptor 563 prolactin-releasing peptide 543 prolyl hydroxylase 43 prostacyclin 132, 398, 490, 565, 567 prostaglandin 309, 310, 328, 398, 512, 565 prostanoid receptor 248, 565 proteasome 49, 460 protein C 568 protein domain 28 protein kinase A80, 129, 144, 171, 177, 183, 184, 225, 243, 246, 266, 289, 309, 327, 389, 452, 466, 543, 609, 720, 721, 724 protein kinase B 178, 206, 422, 460, 506, 510, 532, 543, 564, 582, 609, 628, 633, 661, 667, 717, 724, 752, 773, 803 protein kinase C 73, 80, 120, 129, 144, 171, 183, 185, 226, 229, 244, 246, 262, 266, 325, 336, 420, 473, 480, 496, 509, 530, 609, 629, 633, 639, 681, 763, 805 protein kinase D 286, 473 protein kinase G 171, 177, 246, 266, 411, 676, 681 protein S 803, 804 proteoglycan 725 proteolysis 57 proton-sensing GPCR 551 pseudogene 109 pseudokinase 591, 654 PTen phosphatase 578, 633 PTK7 kinase 593, 650, 742 PTPn1 422, 615, 627, 764 PTPn11/SHP2 206, 421, 511, 527, 626, 628, 633, 634, 637, 639, 764, 786, 789, 803, 805 PTPn2 627, 764 PTPn4 148 PTPn6/SHP1 598, 637, 639, 653, 764, 786, 796, 803, 805 PTPRa 689 PTPRb 260, 601, 646, 661, 691 PTPRc 694, 764 PTPRd 694 PTPRe 695, 764 PTPRf 627, 696 PTPRg 696 PTPRh 696 PTPRj 627, 696 PTPRk 697 PTPRm 697 PTPRn 697 PTPRn2 697 PTPRo 656, 698 PTPRq 698 PTPRr 698 PTPRs 699 PTPRt 699 PTPRu 699 PTPRv 699 PTPRz1 700 pulmonary hypertension 120, 297, 530, 685 purine 474, 482 pyrimidine 482 R R-spondin 739 Rab GTPase 61, 314, 464, 719, 749 Rac GTPase 501, 572, 630, 730, 739, 740 Raf kinase 609 RAMP 514 RapGEF 349 rapsyn 646 Rap GTPase 349, 645 RasA GAP 626, 628 RasGAP 598 Ras GTPase 507, 616, 656, 680 RE1-silencing transcription factor (REST) 248 reactive oxygen species 58, 171, 185, 206, 254, 268, 283, 315, 411, 505, 508, 516, 529, 619, 635, 688, 779, 799 receptor-operated channel 133, 134, 163 receptor for activated C kinase 348 receptor Ser/Thr kinase 366, 662 receptor Tyr kinase 366, 457, 593 receptor Tyr phosphatase 366, 687 recepzyme 362 recoverin 460 reduction–oxidation 58 reelin 335, 349 Index reelin receptor 349 refractory period 186 regulator of G-protein signaling 226, 436, 458, 466, 473, 511 relaxin 573 renin 289, 412, 524 repressilator 66 repulsive guidance molecule 675 resistin 423 resistin receptor 423 respiratory epithelium 634 respiratory neuron 253 retinaldehyde-binding protein 303 retinoic acid 301, 400 retinoic acid-binding protein 302 retinoic acid-related orphan receptor 401 retinoic acid receptor 301, 400, 676 retinoid 301 retinoid X receptor .301, 321, 400 retinol-binding protein 301 retromer 347 ReT receptor 650 RhoGEF 752 Rho GTPase 153, 501, 572, 730, 739, 749, 752 RIBP adaptor 789 RIP kinase 798 RNA-binding protein 60 RNA operon/regulon 60 RoCK kinase 494, 567 ROMK channel 226, 266, 287, 327 RON (MSt1R) kinase 595, 634, 803 ROR (RTK) 535, 741 Ros kinase 653 Runx transcription factor 683 ryanodine receptor 180, 248, 264 RYK kinase 535, 651, 652, 741 S S100 protein 189, 418 SAP adaptor 804 sarcolipin 194 SARM adaptor 792 SAR GTPase 403 scaffold protein 28, 73, 144 scavenger receptor 350, 399, 403, 405, 407, 537 SCF receptor 638 SCF Ub ligase 379, 666, 732, 799 979 Schnurri transcription factor 264 sclerostin 345 secretase .336, 611, 613, 627, 706 secreted Fz-related protein 738, 746 secretin 537, 589 Sef inhibitor 624 selenoprotein 192 semaphorin 628, 649, 650, 751 senescence 750 SERCA pump 156, 186, 193 serotonin 84, 225, 243, 296, 399, 574 serotonin 5HT3 channel 149 serotonin 5HT receptor 297 serotonin transporter 297 serpin 339, 415, 711 serum amyloid-A 546 Ser protease 201, 204 SGK kinase 203, 226, 288 SH3BP2 adaptor 789 SHB adaptor 790 SHC adaptor 40, 341, 507, 526, 603, 626, 644, 651 shear 86 SHIP phosphatase 633, 787, 805 SIAH Ub ligase 378, 790 sialidase 39 sialylation 39, 328 siglec 770 signaling specificity 68 signaling robustness 64 sinoatrial node 138 sirtuin 708, 740 SIT adaptor 789 SK channel 220, 225, 249 SLAM receptor 804 SLA adaptor 790 SLC transporter 155, 266, 274, 393 SMAD factor 34, 38, 79, 299, 344, 378, 678 Smoothened 464, 719, 722 smooth muscle cell .83, 84, 91, 108, 125, 130–132, 167, 171, 181, 185, 187, 196, 198, 199, 206, 213, 230, 238, 243, 248, 249, 315, 341, 390, 413, 417, 452, 473, 490, 492, 506, 508, 528, 532, 563, 570, 619, 644, 709, 739, 765 SMURF Ub ligase 616, 666, 671, 672 Snail homolog (Snai) 683 SOCS 422, 639, 762, 803 980 Index sodium 81, 125, 157, 266 soluble adenylate cyclase 412 soluble guanylate cyclase 410 somatostatin 225, 579 sorcin 191 SOS GEF 32, 33, 527, 601, 604, 606, 628, 633, 788 Sox transcription factor 743 SP1 transcription factor 299 SPCA pump 156, 196 spectrin 666 sphingomyelinase 779 sphingosine 1-phosphate 320, 410, 580 spindle checkpoint 52, 749 spinophilin 466 Sprouty 601, 624 SPURT sensor 204 Src kinase 58, 147, 178, 208, 214, 226, 237, 349, 381, 389, 390, 417, 460, 503, 504, 526, 527, 609, 614, 616, 619, 623, 626, 653, 656, 685, 689, 694, 695, 789, 802 SREBP factor 321, 393 STAMBP deubiquitinase 609 STAM adaptor 604 STAT factor51, 322, 421, 436, 611, 616, 626, 629, 639, 658, 694, 709, 762, 763, 803 Stefan-Maxwell equation 268 stem cell 206 stem cell factor 638 steroid 363, 386 sterol regulatory element-binding protein (SREBP) 322 StIM Ca++ sensor 110, 163 STK39/SPAK kinase 287 store-operated channel 113, 119, 134, 162, 163, 187 stretch-activated ion channels 107 substance P 83, 117, 369, 524, 584 sulfation 46 SUMo 54, 237, 253, 632 sumoylation 54, 671 SUMo sentrin-specific protease 54 superoxide dismutase 85, 283, 284 surfactant 320, 322 surfactant protein 322, 400 Swi–SNF chromatin-remodeler 379 SYK kinase 694, 786, 789, 802 sympathetic 83, 533, 650 sympathoexcitatory reflex 512 symporter 92 synaptojanin 658 synaptotagmin .314 syndecan 625, 645 syntaxin 266 syntrophin 196 T T-cell factor (TCF) 743 tachykinin receptor 584 TAM receptor 803 TATA box-binding protein (TBP) 743 TCR receptor 805 tenascin 691 testicular receptor 391 tetraspanin 615, 639, 772 TGF receptor 662 thermosensitive ion channel 112, 127, 131 thioredoxin 46, 120 thioredoxin-interacting protein 799 thrombin 568, 625 thrombospondin 341, 354, 356, 706 thromboxane 243, 248, 491, 565, 567 thrombus 178 thymosin 563 thyroid-stimulating hormone 539 thyroid hormone 202, 386, 555 thyroid transcription factor (TTF) 322 thyrotropin-releasing hormone 555 TIAM GEF 628, 630 TIE receptor 660, 693 tight junction 306 TIRAP adaptor 792 tissue factor 568, 573 tissue plasminogen activator 415 TNFαIP DUb/Ub ligase 52 TNFRSF 30, 630, 773 TNFSF 630 Toll-like receptor 358, 790, 804 trace amine 585 trachea 262, 263 tracheobronchial tree 262 TRAF Ub ligase 30, 50, 644, 671, 758, 771, 773, 777, 778, 780, 781, 794, 795 TRAM adaptor 792 trans-acting factor 59 transceptor 273 transcription factor 61, 372 Index transducisome 27 transferrin 285 transferrin receptor 285 transforming growth factor 248, 264, 299, 344, 508, 662 transmembrane electric potential difference 94 transporter 92 transthyretin 302 transverse tubule .260 TRAT adaptor 789 Trb adaptor 685 TREM receptor 801 triadin 190 tricarboxylic acid cycle 162 TRIF adaptor 792 triglyceride 350 TRIM Ub ligase 683 troponin 188 TRP channel 42, 108, 172, 248, 308, 348, 410, 434, 564 trypsin 204, 568 tryptase 420, 455 tubulin 211 tumor-necrosis factor 297, 325, 331 tumor cell 439, 603, 622, 630, 751, 796 Tweety homolog channel 260 TyK2 kinase 563 tyramine 585 TyrO3 (RTK) 596, 642, 803 tyrosylprotein sulfotransferase 47 U ubiquitin 59, 61, 63, 615, 737 ubiquitination 21, 47, 463, 671, 708, 738 UCH deubiquitinase 52 UCK kinase 616 uniporter 92 uPA receptor 342 urmylation 56 urocortin 521 urodilatin 408 urokinase .342, 415 urotensin 586 USP deubiquitinase 52, 463, 609, 615, 738 V VangL 741 981 vascular endothelial growth factor 249, 398, 636, 650 vascular smooth muscle cell 85, 120, 131, 134, 166, 176, 211, 213, 230, 237, 259, 297, 342, 419, 479, 509, 527, 619, 657, 658 vascular tone 113, 237, 243, 245, 248, 522 vasculogenesis 548, 635, 700 vasoactive intestinal peptide 83, 546, 588 vasoactive stimulatory phosphoprotein 411 vasoconstriction 85, 119, 120, 134, 185, 246, 248, 297, 451, 473, 496, 506, 529, 530, 544, 557, 567, 570, 586, 587 vasodilation 84, 113, 116, 132, 187, 213, 230, 243, 244, 246, 249, 356, 389, 410, 411, 420, 451, 474, 506, 512, 524, 529, 530, 539, 567, 586, 701 vasopressin 83, 108, 202, 309, 420, 509, 586 vATPase 155, 269 Vav GEF 788, 789, 805 VDAC channel/porin 262 VEGF receptor 636 vesicle 31, 61 vesicular ACh transporter 291, 298 vesicular calcium channel 162 vesicular GABA transporter 291 vesicular glutamate transporter 291 vesicular monoamine transporter 291, 298 VHL Ub ligase 43 visfatin 423 vitamin-A 301, 343, 372, 377, 400 vitamin-B 319, 343, 344, 559 vitamin-C 301, 315 vitamin-D 343, 344, 372, 377, 726 vitamin-E 343, 344 vitronectin 417 VLDL 350 VLDLR receptor 349 voltage-gated channel 103, 199 volume-activated anion channel 82 volume-activated ion channels 107 von Willebrand factor 491 VRAC channel 261, 265 VSOR channel 81 W Willis circle 710 wine polyphenol 389 WNK kinase 120, 226, 286, 287 982 Index Wnt 345, 346, 399, 413, 650–652, 699, 727, 750 Y Yes kinase 358 Z ZAP70 kinase 593, 789 ZBTB factor 413 ZEB factor 78 ZFYVE anchor 665, 667, 672, 679 zinc 116, 147, 149, 152, 267, 304, 720 ZnF adaptor 790 zonula occludens protein 564 zwitterion 294 ... (e.g., fatty and bile acids and sterols), and xenobiotics M Thiriet, Signaling at the Cell Surface in the Circulatory and Ventilatory Systems, Biomathematical and Biomechanical Modeling of the Circulatory. .. cells from their environment During integrin outside? ?in signaling, the binding of integrins to their extracellular ligands changes the integrin conformation and promotes integrin clustering The unidirectional... unidirectional signalings, in fact, are often closely linked, as ligand binding associated with outside? ?in signaling stimulates integrins and, conversely, integrin activation increases ligand binding for inside–out