We Offer Worldwide Shipping
Login Wishlist

alpha-Amyrenyl acetate

$405

  • Brand : BIOFRON

  • Catalogue Number : AV-B01190

  • Specification : 95%

  • CAS number : 863-76-3

  • Formula : C32H52O2

  • Molecular Weight : 468.77

  • PUBCHEM ID : 92842

  • Volume : 5mg

Available on backorder

Quantity
Checkout Bulk Order?

Catalogue Number

AV-B01190

Analysis Method

HPLC,NMR,MS

Specification

95%

Storage

2-8°C

Molecular Weight

468.77

Appearance

Powder

Botanical Source

Structure Type

Triterpenoids

Category

Standards;Natural Pytochemical;API

SMILES

CC1CCC2(CCC3(C(=CCC4C3(CCC5C4(CCC(C5(C)C)OC(=O)C)C)C)C2C1C)C)C

Synonyms

Urs-12-en-3β-ol, acetate/Urs-12-en-3-ol, acetate, (3β)-/Acetic acid,4,4,6a,6b,8a,11,12,14b-octamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydro-picen-3-yl ester/Urs-12-en-3β-ol, acetate (8CI)/(3β)-Urs-12-en-3-yl acetate/4,4,6a,6b,8a,11,12,14b-octamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl acetate/α-Amyrin acetate/Urs-12-en-3-yl acetate

IUPAC Name

[(3S,4aR,6aR,6bS,8aR,11R,12S,12aR,14aR,14bR)-4,4,6a,6b,8a,11,12,14b-octamethyl-2,3,4a,5,6,7,8,9,10,11,12,12a,14,14a-tetradecahydro-1H-picen-3-yl] acetate

Applications

α-Amyrin acetate, a natural triterpenoid, has anti-inflammatory activity, antispasmodic profile and the relaxant effect[1][2].

Density

1.0±0.1 g/cm3

Solubility

Soluble in Chloroform,Dichloromethane,Ethyl Acetate,DMSO,Acetone,etc.

Flash Point

258.0±17.7 °C

Boiling Point

508.0±50.0 °C at 760 mmHg

Melting Point

241ºC

InChl

InChl Key

UDXDFWBZZQHDRO-UHFFFAOYSA-N

WGK Germany

RID/ADR

HS Code Reference

Personal Projective Equipment

Correct Usage

For Reference Standard and R&D, Not for Human Use Directly.

Meta Tag

provides coniferyl ferulate(CAS#:863-76-3) MSDS, density, melting point, boiling point, structure, formula, molecular weight etc. Articles of coniferyl ferulate are included as well.>> amp version: coniferyl ferulate

No Technical Documents Available For This Product.

Title

ESICM LIVES 2016: part two Milan, Italy. 1-5 October 2016

Author

S. Sivakumar,1 F. S. Taccone,2 K. A. Desai,1 C. Lazaridis,corresponding author1 M. Skarzynski,corresponding author3 M. Sekhon,4 W. Henderson,4 D. Griesdale,4 L. Chapple,corresponding author5 A. Deane,5,6 L. Williams,7 R. Strickland,6 K. Lange,8 D. Heyland,9 M. Chapman,5,6 M. J. Rowland,corresponding author10,11 P. Garry,10,11 J. Westbrook,10,11 R. Corkill,11 C. A. Antoniades,10,11 K. T. Pattinson,10,11 G. Fatania,corresponding author12 A. J. Strong,13 R. B. Myers,14 C. Lazaridis,corresponding author15 C. M. Jermaine,14 C. S. Robertson,16 C. G. Rusin,17 J. Hofmeijer,corresponding author18,19 L. Sondag,19 M. C. Tjepkema-Cloostermans,20 A. Beishuizen,21 F. H. Bosch,22 M. J. A. M. van Putten,18,20 L. Carteron,corresponding author23 C. Patet,23 D. Solari,23 M. Oddo,23 M. A. Ali,corresponding author24 C. Dias,corresponding author25,26 R. Almeida,27,28,29 A. Vaz-Ferreira,30 J. Silva,30 E. Monteiro,25,26 A. Cerejo,31,32 A. P. Rocha,28,33 A. A. Elsayed,34 A. M. Abougabal,35 B. N. Beshey,34 K. M. Alzahaby,corresponding author34 S. Pozzebon,corresponding author36 A. Blandino Ortiz,36 S. Cristallini,36 O. Lheureux,36 A. Brasseur,36 J. L. Vincent,36 J. Creteur,36 F. S. Taccone,36 M. Hravnak,corresponding author37 K. Yousef,37 Y. Chang,38 E. Crago,37 R. M. Friedlander,38 S. A. Abdelmonem,corresponding author39 S. A. Tahon,40 T. A. Helmy,39 H. S. Meligy,39 F. Puig,corresponding author41 I. Dunn-Siegrist,41 J. Pugin,41,42 S. Gupta,corresponding author43 D. Govil,43 S. Srinivasan,43 S. J. Patel,43 J. K. N,43 A. Gupta,43 D. S. Tomar,43 M. Shafi,43 R. Harne,43 D. P. Arora,43 N. Talwar,43 S. Mazumdar,43 E. E. Papakrivou,corresponding author44 D. Makris,44 E. Manoulakas,44 B. Tsolaki,44 B. Karadodas,44 E. Zakynthinos,44 I. Palacios Garcia,corresponding author45 A. Diaz Martin,45 V. Sanchez Encinares,45 M. Pachon IbaNez,45 J. Garnacho Montero,45 G. Labrador,45 T. Cebrero Cangueiro,45 V. Poulose,corresponding author46 J. Koh,46 J. W. Kam,47 H. Yeter,corresponding author48 A. Kara,49 O. Aktepe,50 A. Topeli,51 I. Tsolakoglou,corresponding author52 G. Intas,53 P. Stergiannis,54 A. A. Kolaros,55 E. Chalari,56 E. Athanasiadou,57 A. Martika,52 G. Fildisis,58 V. Faivre,corresponding author59 C. Mengelle,59 B. Favier,60 D. Payen,59,61 A. Poppe,corresponding author62 M. S. Winkler,62 E. Mudersbach,63 J. Schreiber,64 M. L. Wruck,62 E. Schwedhelm,63 S. Kluge,64 C. Zollner,62 T. Tavladaki,corresponding author65 A. M. Spanaki,65 H. Dimitriou,66 E. Kondili,67 C. Choulaki,68 E. Meleti,66 D. Kafetzopoulos,68 D. Georgopoulos,67 G. Briassoulis,65 A. Garcia-de la Torre,corresponding author69 M. V. de la Torre-Prados,70 T. Tsvetanova-Spasova,70 P. Nuevo-Ortega,70 C. Rueda-Molina,70 A. Fernandez-Porcel,70 E. Camara-Sola,70 L. Salido-Diaz,70 A. Garcia-Alcantara,70 T. Tavladaki,corresponding author71 A. M. Spanaki,71 H. Dimitriou,72 E. Kondili,73 C. Choulaki,74 D. E. Meleti,72 D. Kafetzopoulos,72 D. Georgopoulos,73 G. Briassoulis,71 B. Suberviola,corresponding author75 J. Riera,76 L. Rellan,77 M. Sanchez,78 J. C. Robles,79 E. Lopez,80 R. Vicente,81 E. MiNambres,75 M. SantibaNez,82 M. Le Guen,corresponding author83 J. Moore,83 N. Mason,83 M. Windpassinger,corresponding author84 O. Plattner,84 E. Mascha,85 D. I. Sessler,85 Outcomes Research, U. Melia,corresponding author86 J. Fontanet,86 J. P. van den Berg,87 M. M. R. F. Struys,87,88 H. E. M. Vereecke,87,88 E. W. Jensen,86,89 P. J. T. Rood,corresponding author90 F. van de Schoor,90 K. van Tertholen,90 P. Pickkers,90 M. van den Boogaard,90 Z. J. Beardow,corresponding author91 H. Redhead,91 K. Paramasivam,91 T. Numan,92 M. van den Boogaard,93 A. M. Kamper,94 P. Rood,93 L. M. Peelen,92 P. M. Zeman,95 A. J. Slooter,corresponding author92 C. E. van Ewijk,corresponding author96 G. E. Jacobs,97,98 A. R. J. Girbes,96 S. N. Myatra,corresponding author99 M. M. Harish,99 N. R. Prabu,99 S. Siddiqui,99 A. P. Kulkarni,99 J. V. Divatia,99 L. D. Murbach,corresponding author100 M. A. Leite,100 E. F. Osaku,100 C. R. L. M. Costa,100 M. Pelenz,100 N. M. Neitzke,100 M. M. Moraes,100 J. L. Jaskowiak,100 M. M. M. Silva,100 R. S. Zaponi,100 L. R. L. Abentroth,100 S. M. Ogasawara,100 A. C. Jorge,100 P. A. D. Duarte,100 N. Hernandez-Sanchez,corresponding author101 L. A. Sanchez-Hurtado,101 F. J. Garcia-Guillen,101 S. A. Namendys-Silva,101 B. Maghsoudi,corresponding author102 M. Emami,102 M. B. Khosravi,102 F. Zand,102 H. R. Tabatabaie,103 M. Masjedi,102 G. Sabetiyan,102 A. Mokri,104 Nurses of the Central and General ICUs of Shiraz Namazi Hospital, J. Troubleyn,corresponding author105 M. Diltoer,105 R. Jacobs,105 D. N. Nguyen,105 E. De Waele,105 J. De Regt,105 P. M. Honore,105 V. Van Gorp,105 H. D. Spapen,105 R. S. Contreras,corresponding author106 N. D. Toapanta,106 G. Moreno,106 J. Sabater,106 H. Torrado,106 M. Gonzalez,106 M. Marin,106 E. Farigola,106 A. Gonzalez,106 J. Fernandez,106 A. Vera,106 X. Gisbert,106 C. Julia,106 J. Uya,106 L. Corral,106 Sedation an Delirium Group Hospital Universitari de Bellvitge, I. Elias-Jones,corresponding author107 L. Gemmell,107 A. MacKay,107 D. Randall,108 A. Adwaney,108 M. Blunden,108 J. R. Prowle,108,109 C. J. Kirwan,corresponding author108,109 N. Thomas,corresponding author110 A. Martin,111 H. Owen,111 L. Darwin,111 D. Conway,110 D. Atkinson,110 M. Sharman,110 J. Moore,110 C. Barbanti,corresponding author112 J. Amour,113 P. Gaudard,114 B. Rozec,115 P. Mauriat,116 M. M’rini,117 P. L. Leger,118 G. Cambonie,119 J. M. Liet,120 C. Girard,121 S. Laroche,122 P. Damas,123 Z. Assaf,124 G. Loron,125 L. Lecourt,126 P. Pouard,127 D. Randall,128 A. Adwaney,128 M. Blunden,128 J.R. Prowle,128,129 C. J. Kirwan,corresponding author128,129 S. H. Kim,corresponding author130 S. Na,130 J. Kim,130 S. Y. Oh,corresponding author131 C. W. Jung,132 S. H. Yoo,132 S. H. Min,132 E. J. Chung,132 H. Lee,132 N. J. Lee,131 K. W. Lee,131 K. S. Suh,131 H. G. Ryu,132 D. C. Marshall,133 R. J. Goodson,133 J. D. Salciccioli,corresponding author133 J. Shalhoub,133 E. K. Potter,corresponding author134,135 J. Kirk-Bayley,134,136 N. D. Karanjia,134,136 L. G. Forni,134,136 B. C. Creagh-Brown,134,136 M. Bossy,corresponding author137 M. Nyman,138 A. Tailor,139 B. Creagh-Brown,140 SPACeR group (Surrey Peri-operative, Anaesthesia and Critical Care Collaborative Research Group), D. D’Antini,corresponding author142 S. Spadaro,143 F. Valentino,142 F. Sollitto,144 G. Cinnella,142 L. Mirabella,142 F. J. Redondo Calvo,corresponding author145 N. Bejarano,146 D. Padilla,147 V. Baladron,148 P. Villajero,147 R. Villazala,148 J. Redondo,148 A. S. Yuste,148 J. Liu,149,150 F. Shen,149,151 J. L. Teboul,149 N. Anguel,149 A. Beurton,149 N. Bezaz,149 C. Richard,149 X. Monnet,corresponding author149 T. Fossali,corresponding author152 R. Colombo,152 D. Ottolina,152 M. Rossetti,152 C. Mazzucco,153 A. Marchi,153 A. Porta,154 E. Catena,152 K. H. Tollisen,corresponding author155 G. Ø. Andersen,156 F. Heyerdahl,157 D. Jacobsen,158 M. C. de Waard,corresponding author159 A. R. J. Girbes,159 M. C. O. van IJzendoorn,corresponding author160,161 H. Buter,160 W. P. Kingma,160 G. J. Navis,161 E. C. Boerma,160 J. Rulisek,corresponding author162 M. Balik,163,164 S. Zacharov,165 H. S. Kim,corresponding author166 S. J. Jeon,166 H. Namgung,166 E. Lee,166 E. Lee,167 Y. J. Cho,168 Y. J. Lee,168 A. Huang,169,170 L. Cioccari,corresponding author169,171 N. Luethi,169 J. Martensson,169,172 R. Bellomo,169,173 M. Forsberg,corresponding author174 G. Edman,174 J. Hojer,175,176 S. Forsberg,176,177 M. T. Chiquito Freile,corresponding author178 F. N. Hidalgo,178 J. A. Martinez Molina,178 R. Lecumberri,179 A. Figuerola Rossello,178 P. Medrano Travieso,178 G. Tuero Leon,corresponding author180 J. Gonzalez Sanchez,180 L. Sahuquillo Frias,181 D. Balsells Rosello,181 J. A. Garcia Verdejo,180 J. A. Noria Serrano,180 D. Winterwerp,corresponding author182 T. van Galen,183 A. Vazin,corresponding author184 I. Karimzade,185 A. Zand,185 E. Ozen,corresponding author186 S. Ekemen,186 A. Akcan,186 E. Sen,186 B. Buyukkidan Yelken,186 N. Kureshi,187,188 L. Fenerty,187 G. Thibault-Halman,187 M. Erdogan,189 S. Walling,187 R. S. Green,corresponding author188,189 D. B. Clarke,187 P. Briassoulis,corresponding author190 K. Kalimeris,190 A. Ntzouvani,191 T. Nomikos,191 K. Papaparaskeva,192 E. Politi,193 G. Kostopanagiotou,190 K. Crewdson,corresponding author194 M. Rehn,194 A. Weaver,194 K. Brohi,194 D. Lockey,194 S. Wright,195 K. Thomas,195 C. Baker,195 L. Mansfield,195 V. Stafford,195 C. Wade,195 G. Watson,196 A. Bryant,197 T. Chadwick,197 J. Shen,197 J. Wilkinson,196 J. Furneval,198 A. Henderson,198 K. Hugill,199 P. Howard,199 A. Roy,198 S. Bonner,199 S. Baudouin,corresponding author195 C. Sanchez Ramirez,corresponding author200 S. Hipola Escalada,200 M. A. Hernandez Viera,200 M. Cabrera Santana,200 L. Caipe Balcazar,200 N. Sangil Monroy,201 F. Artiles Campelo,202 C. F. L?bbe Vazquez,200 P. Saavedra Santana,203 S. Ruiz Santana,200 L. Carteron,corresponding author204 C. Patet,204 H. Quintard,205 D. Solari,204 P. Bouzat,206 M. Oddo,204 T. Wollersheim,corresponding author207,208 J. Malleike,207 K. Haas,207 N. Carbon,207 J. Schneider,207,208 C. Birchmeier,209 J. Fielitz,210,211 S. Spuler,207,210 S. Weber-Carstens,207,208 L. EnseNat,corresponding author212 A. Perez-Madrigal,212 P. Saludes,212 L. Proen?a,212,213 G. Gruartmoner,212 C. Espinal,212 J. Mesquida,212 W. Huber,corresponding author214 M. Eckmann,214 F. Elkmann,214 A. Gruber,214 T. Lahmer,214 U. Mayr,214 A. Herner,214 R. Schellnegger,214 J. Schneider,214 R. M. Schmid,214 W. Ayoub,corresponding author215 W. Samy,215 A. Esmat,216 A. Battah,217 S. Mukhtar,217 W. Mongkolpun,corresponding author218 D. Orbegozo Cortes,218 C. P. R. Cordeiro,218 J. L. Vincent,218 J. Creteur,218 S. Funcke,corresponding author219 H. Groesdonk,220 B. Saugel,219 G. Wagenpfeil,221 S. Wagenpfeil,221 D. A. Reuter,219 M. M. Fernandez,corresponding author222 R. Fernandez,223 M. Magret,224 A. Gonzalez-Castro,225 M. T. Bouza,226 M. IbaNez,227 C. Garcia,228 B. Balerdi,229 A. Mas,230 V. Arauzo,231 J. M. ANon,232 F. Ruiz,233 J. Ferreres,234 R. Tomas,235 M. Alabert,236 A. I. Tizon,237 S. Altaba,238 N. Llamas,239 E C. Goligher,corresponding author240 E. Fan,240 M. Herridge,240 S. Vorona,240 M. Sklar,240 M. Dres,240,241 N. Rittayamai,240 A. Lanys,240 C. Urrea,240 G. Tomlinson,242 W. D. Reid,243 G. D. Rubenfeld,240 B. P. Kavanagh,240 L. J. Brochard,240 N. D. Ferguson,240 A. Serpa Neto,corresponding author244,245 M. Gama de Abreu,246 P. Pelosi,247 M. J. Schultz,245 for the PRoVENT investigators and the PROVE Network, C. Guerin,corresponding author248,249 L. Papazian,250 J. Reignier,251 L. Ayzac,252 A. Loundou,250 J. M. Forel,250 C. Rolland-Debord,253 C. Bureau,corresponding author253 T. Poitou,253 M. Clavel,254 S. Perbet,255 N. Terzi,256 A. Kouatchet,257 T. Similowski,253 A. Demoule,253 N. Hunfeld,corresponding author258,259 Z. Trogrlic,258 S. Ladage,258 R. J. Osse,260 B. Koch,259 W. Rietdijk,258 J. Devlin,261 M. van der Jagt,258 E. Picetti,corresponding author262 P. Ceccarelli,262 F. Mensi,262 L. Malchiodi,262 S. Risolo,262 I. Rossi,262 M. V. Antonini,262 F. Servadei,263 M. L. Caspani,262 A. Roquilly,corresponding author264 S. Lasocki,265 P. Seguin,266 T. Geeraerts,267 P. F. Perrigault,268 C. Dahyot-Fizelier,269 C. Paugam-Burtz,270 F. Cook,271 R. Cinotti,272 D. Demeure dit Latte,272 P. J. Mahe,272 C. Fortuit,272 F. Feuillet,272 K. Asehnoune,272 C. Marzorati,corresponding author273 S. Spina,273 V. Scaravilli,273 A. Vargiolu,274 M. Riva,273 C. Giussani,273,275 E. Sganzerla,273,275 G. Citerio,273,274 S. Barbadillo,corresponding author276 F. J. Gonzalez de Molina,277,278 F. alvarez-Lerma,279 A. Rodriguez,280 SEMICYUC/GETGAG Working Group, T. Zakharkina,281 I. Martin-Loeches,282 S. Matamoros,281 P. Povoa,283 A. Torres,284 J. Kastelijn,281 J. J. Hofstra,281 M. de Jong,281 M. Schultz,281 P. Sterk,281 A. Artigas,285 L. J. Bos,corresponding author281 A. S. Moreau,corresponding author286 I. Martin-Loeches,287 P. Povoa,288 J. Salluh,289 A. Rodriguez,290 S. Nseir,286 TAVeM study group, E. de Jong,corresponding author291 J. A. van Oers,292 A. Beishuizen,293 A. R. J. Girbes,291 M. W. N. Nijsten,294 D. W. de Lange,295 D. Bonvicini,296 D. Labate,corresponding author296 L. Benacchio,297 A. Olivieri,297 E. Pizzirani,296 J. C. Lopez-Delgado,corresponding author298 M. Gonzalez-Romero,298 V. Fuentes-Mila,298 D. Berbel-Franco,298 I. Romera-Peregrina,298 A. Martinez-Pascual,298 J. Perez-Sanchez,298 R. Abellan-Lencina,298 R. E. avila-Espinoza,298 G. Moreno-Gonzalez,298 F. Sbraga,299 S. Griffiths,300 M. P. W. Grocott,300,301 B. Creagh-Brown,corresponding author302,303 POPC-CB investigators, J. Doyle,corresponding author304 P. Wilkerson,305 Y. Soon,305 S. Huddart,306 M. Dickinson,306 A. Riga,307 A. Zuleika,308 K. Miyamoto,corresponding author309 Y. Kawazoe,310 T. Morimoto,311 T. Yamamoto,312 A. Fuke,313 A. Hashimoto,314 H. Koami,315 S. Beppu,316 Y. Katayama,317 M. Ito,318 Y. Ohta,319 H. Yamamura,320 DESIRE (DExmedetomidine for Sepsis in ICU Randomized Evaluation) Trial Investigators, S. L. Rygard,corresponding author321 L B. Holst,321 J. Wetterslev,322 P. I. Johansson,323 A. Perner,321 I. W. Soliman,corresponding author324 D. W. de Lange,324 D. van Dijk,324 J. J. M. van Delden,325 O. L. Cremer,324 A. J. C. Slooter,324 L. M. Peelen,324,326 D. McWilliams,327 C. Snelson,corresponding author328 A. Das Neves,corresponding author329 C. I. Loudet,329 M. Busico,330 D. Vazquez,331 D. Villalba,332 M. Veronesi,333 A. Lischinsky,334 F. J. L. Lopez,335 L. Benito Mori,336 G. Plotnikow,331 A. Diaz,337 S. Giannasi,338 R. Hernandez,339 L. Krzisnik,340 C. Cecotti,341 L. Viola,342 R. Lopez,343 J. P. Sottile,344 G. Benavent,345 E. Estenssoro,329 C. M. Chen,corresponding author346,347 C. C. Lai,348 K. C. Cheng,349 W. Chou,346 K. S. Chan,347 L. E. Roeker,corresponding author350 C. M. Horkan,350 F. K. Gibbons,351 K. B. Christopher,352,353 P. J. M. Weijs,corresponding author354,355 K. M. Mogensen,356 J. D. Rawn,357 M. K. Robinson,357 K. B. Christopher,358,359 Z. Tang,corresponding author360 C. Qiu,360 B. Ouyang,360 C. Cai,360 X. Guan,360 T. Regueira,corresponding author361 L. Cea,362 S. Juan Carlos,363 B. Elisa,363 C. Puebla,363 A. Vargas,363 M. K. Poulsen,364 L. P. Thomsen,364 S. Kjærgaard,365 S. E. Rees,corresponding author364 D. S. Karbing,364 T. Wollersheim,corresponding author366,367 S. Frank,366 M. C. M?ller,366 N. M. Carbon,366 V. Skrypnikov,366 P. A. Pickerodt,366 R. Falk,366 A. Mahlau,366 S. Weber-Carstens,366,367 A. Lee,corresponding author368 R. Inglis,368 R. Morgan,368 G. Barker,368 K. Kamata,corresponding author369 T. Abe,370,371 D. Saitoh,372 Y. Tokuda,373 R. S. Green,corresponding author374 M. B. Butler,375 M. Erdogan,374 H. Tae Hwa,corresponding author376 L. Jae Gil,376 R. Hernandez Vaquero,corresponding author377 E. Rodriguez-Ruiz,377 A. Lopez Lago,377 J. L. Garcia Allut,377 A. Estany Gestal,378 M. A. Garcia Gonzalez,379 D. O. Thomas-R?ddel,corresponding author380,381 D. Schwarzkopf,381 C. Fleischmann,380,381 K. Reinhart,380,381 S. Suwanpasu,corresponding author382 Y. Sattayasomboon,383 N. M. Filgueiras Filho,corresponding author384,385 J. C. A. Oliveira,384 C. S. Ballalai,384,385 C. V. De Lucia,384,385 G. P. Araponga,384 L. N. Veiga,384 C. S. Silva,384,385 M. E. Garrido,384,385 B. B. Ramos,384,385 E. F. Ricaldi,384,385 S. S. Gomes,384,385 GEMINI, L. Gemmell,corresponding author386 A. MacKay,386 C. Wright,386 R. I. Docking,386 P. Doherty,386 E. Black,386 P. Stenhouse,386 M. P. Plummer,corresponding author387,388 M. E. Finnis,387,388 L. K. Phillips,389,390 P. Kar,387,388 S. Bihari,391,392 V. Biradar,393 S. Moodie,388 M. Horowitz,389,390 J. E. Shaw,394 A. M. Deane,387,388 T. Yatabe,corresponding author395 S. Inoue,396 M. Sakaguchi,397 M. Egi,398 Y. Ali Abdelhamid,corresponding author399,400 M. P. Plummer,399,400 M. E. Finnis,399,400 L. K. Phillips,401,402 P. Kar,399,400 S. Bihari,403,404 V. Biradar,405 S. Moodie,399 M. Horowitz,401,402 J. E. Shaw,406 A. M. Deane,399,400 M. Hokka,corresponding author407 M. Egi,407 S. Mizobuchi,407 P. Kar,corresponding author408,409 M. Plummer,410 Y. Ali Abdelhamid,408,409 E. Giersch,408 M. Summers,408 S. Hatzinikolas,411 S. Heller,412 M. Chapman,408,409,411 K. Jones,411,413 M. Horowitz,411,413 A. Deane,408,409,411 R. Schweizer,corresponding author414 M. Jacquet-Lagreze,414 P. Portran,414 S. Junot,415 B. Allaouchiche,416 J. L. Fellahi,414 P. Guerci,corresponding author417,418,419 B. Ergin,417 A. Kapucu,420 C. Ince,417 L. Cioccari,corresponding author421,422 N. Luethi,421 M. Crisman,421,423 R. Bellomo,421,424 J. Martensson,421,425 C. Righy Shinotsuka,corresponding author426 D. Fagnoul,426 A. Brasseur,426 D. Orbegozo,426 J. L. Vincent,426 J. C. Preiser,426 J. C. Preiser,corresponding author427 O. Lheureux,427 A. Thooft,427 S. Brimioulle,427 J. L. Vincent,427 H. Iwasaka,corresponding author428 S. Tahara,429 M. Nagamine,429 A. Ichigatani,429 A. Rugerio Cabrera,corresponding author430 E. Monares Zepeda,430 J. Franco Granillo,430 J. S. Aguirre Sanchez,430 A. A. Tanaka Montoya,430 A. Pedraza Montenegro,430 G. A. Galvez Blanco,430 C. M. Coronado Robles,430 A. Drolz,corresponding author431,432 T. Horvatits,431,432 K. Roedl,431,432 K. Rutter,431,432 S. Kluge,432 G. C. Funk,433 B. Schneeweiss,431 V. Fuhrmann,431,432 G. Sabetian,corresponding author434 F. Pooresmaeel,435 F. Zand,436 S. Ghaffaripour,435 A. Farbod,435 H. Tabei,435 L. Taheri,corresponding author437 R. Anandanadesan,437 V. Metaxa,437 C. Teixeira,corresponding author438,439,440 S. M. Pereira,438 P. Hernandez-Marrero,438,441 A. S. Carvalho,438 M. Beckmann,corresponding author442 C. S. Hartog,443 D. Schwarzkopf,443 A. Raadts,442 A. Robertsen,corresponding author444 R. Førde,445 N. O. Skaga,444 E. Helseth,446 S. Honeybul,corresponding author447 K. Ho,448 P. Martinez Lopez,449 M. Nieto Gonzalez,corresponding author449 P. Nuevo Ortega,449 E. Camara Sola,449 T. Spasova,449 M. V. de la Torre-Prados,449 O. Kopecky,450 K. Rusinova,corresponding author450 P. Waldauf,451 Z. Cepeplikova,450 M. Balik,450 J. Palamidessi Dominguez,corresponding author452 P. Matia Almudevar,452 S. Alcantara Carmona,452 J. J. Rubio MuNoz,452 D. Palacios CastaNeda,452 A. Naharro Abellan,452 P. Rodriguez Villamizar,452 J. Veganzones Ramos,452 L. Perez Perez,452 A. Perez Lucendo,452 M. Camos Ejarque,452 A. Estella,corresponding author453 V. Lopez Camps,454 M. C. Martin,455 N. Masnou,456 Bioethics work group of SEMICYUC, S. Barbosa,corresponding author457 A. Varela,457 I. Palma,457 L. Cristina,457 E. Nunes,457 I. Pereira,457 G. Campello,458 C. Granja,457,459,460 R. Pande,corresponding author461 M. Pandey,462 S. Varghese,461 M. Chanu,461 M. J. Van Dam,corresponding author463,464 E. W. M. T. Ter Braak,464,465 A. Estella,corresponding author466 M. Gracia,466 R. Viciana,467 M. Recuerda,466 L. Perez FontaiNa,466 B. Tharmalingam,corresponding author468 F. Kovari,469 L. Rose,corresponding author470 M. Mcginlay,471 R. Amin,472 K. Burns,473 B. Connolly,474 N. Hart,474 P. Jouvet,475 S. Katz,476 D. Leasa,477 C. Mawdsley,477 D. Mcauley,478 M. Schultz,479 B. Blackwood,478 S. Denham,corresponding author480 R. Worrall,480 M. Arshad,480 P. Isherwood,480 A. Khadjibaev,corresponding author481 D. Sabirov,482 A. Rosstalnaya,482 F. Parpibaev,481 V. Sharipova,481 G. A. Galvez Blanco,corresponding author483 C. I. Olvera Guzman,483 J. S. Aguirre Sanchez,483 J. Franco Granillo,483 S. Gupta,corresponding author484 D. Govil,484 S. Srinivasan,484 S. J. Patel,484 J. K. N,484 A. Gupta,484 M. Shafi,484 D. S. Tomar,484 R. Harne,484 D. P. Arora,484 N. Talwar,484 S. Mazumdar,484 Y. S. Cha,corresponding author485 S. J. Lee,486 N. Tyagi,corresponding author487 R. K. Rajput,487 S. Taneja,487 V. K. Singh,487 S. C. Sharma,487 S. Mittal,487 B. K. Rao,487 J. Ayachi,corresponding author488 N. Fraj,488 S. Romdhani,488 A. Khedher,488 K. Meddeb,488 N. Sma,488 A. Azouzi,488 R. Bouneb,488 I. Chouchene,488 M. El Ghardallou,489 M. Boussarsar,488,490 R. Jennings,corresponding author491 E. Walter,491 J. M. Ribeiro,corresponding author492 I. Moniz,492 R. Mar?al,492 A. C. Santos,492 C. Candeias,492 Z. Costa e Silva,492 S. E. Zamora Gomez,corresponding author493 O. R. Perez Nieto,493 J. A. Castanon Gonzalez,493 A. I. Vasquez Cuellar,493 H. Mildh,corresponding author494 V. Pettil?,494,495 A. M. Korhonen,494 S. Karlsson,496 T. Ala-Kokko,497 M. Reinikainen,498 S. T. Vaara,494 The FINNAKI Study Group, M. Zaleska-Kociecka,corresponding author499 M. Grabowski,500 M. D?browski,501 S. Wozniak,502 K. Piotrowska,503 M. Banaszewski,499 J. Imiela,504 J. Stepinska,499 A. Gonzalez Perez,corresponding author505 P. Florez OrdoNez,505 A. Giribet,505 M. A. Alonso Cuervo,505 R. Alonso Cuervo,505 M. A. Rodriguez Esteban,505 L. Iglesias Fraile,505 C. Ponte Mittelbrum,505 G. MuNiz Albaiceta,505 J. Koeze,corresponding author506 F. Keus,506 W. Dieperink,506 I. C. C. van der Horst,506 M. van Meurs,506 J. G. Zijlstra,506 S. Roberts,507 C. Hernandez Caballero,corresponding author507 G. Isgro,507 D. Hall,507 S. Beitland,corresponding author508,509 A.-M. S. Trøseid,510 B. S. Brusletto,510 B. E. Waldum-Grevbo,511 J. P. Berg,509,510 K. Sunde,508,509 D. Garcia Huertas,corresponding author512 F. Manzano,512 M. M. Jimenez- Quintana,512 A. Osuna,512 F. Santiago-Ruiz,512 C. Rodriguez-Mejias,512 R. Wangensteen,513 H. R. Jamaati,514 M. Masjedi,corresponding author515,516 F. Zand,516,517 S. M. R. Hashemian,514 G. Sabetian,517 G. Abbasi,517 V. Khaloo,517 S. H.a. Tabei,517 A. Kafilzadeh,517 H. Haddad Bakhodaei,517 J. A. Diaz,corresponding author518,519 R. Silva,518,519 D. J. Garcia,518 E. Luis,518 M. N. Gomez,518 R. Soriano,518 P. L. Gonzalez,518 I. A. Ibrahim,520 M. M. Rafik,521 A. M. Al-Ansary,520 M. A. Algendi,corresponding author520 A. A. Ali,522 V. Fuhrmann,corresponding author523 K. Roedl,523 T. Horvatits,523 A. Drolz,523 K. Rutter,523 D. Benten,524 J. Kluwe,524 S. Siedler,523 S. Kluge,523 I. Adedugbe,525 G. T. Bird,corresponding author525 Queen Square Neuroanaesthesia and Neurocritical Care Resreach Group, R. M. Kennedy,526 S. Sharma,526 M. B. Butler,527 G. Yugi,528 B. A. Haroon,527,529 T. Witter,corresponding author527,528 W. Khaliq,corresponding author530 M. Singer,530 A. A. Havaldar,corresponding author531 B. Krishna,531 S. Sriram,531 E. D. Valenzuela Espinoza,532 M. O. Pozo,533 V. S. Kanoore Edul,533 M. Furche,532 M. F. Motta,532 A. Risso Vazquez,532 P. N. Rubatto Birri,532 C. Ince,534 A. Dubin,corresponding author532,533 A. Dogliotti,corresponding author535,536 A. Ramos,537 C. Lovesio,537 E. Delile,corresponding author538 R. Nevi?re,539 P.-A. Thiebaut,538 J. Maupoint,538 P. Mulder,538 D. Coquerel,538 S. Renet,538 J. C. do Rego,540 J. Rieusset,541 V. Richard,538 F. Tamion,542 W. Khaliq,corresponding author543 D. T. Andreis,543,544 M. Singer,543 B. Smit,corresponding author545 Y. M. Smulders,546 M. C. de Waard,545 H. M. Oudemans van Straaten,545 A. R. J. Girbes,545 E. C. Eringa,547 A. M. E. Spoelstra-de Man,545 L. Alegria,corresponding author548 D. Soto,548 C. Luengo,549 J. Gomez,550 N. Jarufe,551 A. Bruhn,548 R. Castro,548 E. Kattan,548 P. Tapia,552 R. Rebolledo,551 P. Achurra,551 G. Ospina-Tascon,553 J. Bakker,548 G. Hernandez,548 P. Bertini,corresponding author554 F. Guarracino,554 R. Baldassarri,554 M. R. Pinsky,555 L. Alegria,corresponding author556 M. Vera,556 J. Dreyse,556 D. Carpio,556 C. Henriquez,556 D. Gajardo,556 S. Bravo,556 R. Castro,556 G. Ospina-Tascon,557 J. Bakker,556 G. Hernandez,556 S. Kim,558 M. Lee,558 S. Y. Park,corresponding author559 S. So,559 H. Lee,559 M. B. Ka?ar,corresponding author562 S. M. Ka?ar,563 I. Uddin,corresponding author564 A. M. Belhaj,565 M. A. Aydın,566 D. Avsec,567 A. Kapua?ası,566 ?. Kaymak,corresponding author566 L. Kovach,568 ?. ?encan,566 B. Me?o,569 M. oz?elik,569 N. ?nal,569 C. Lazaridis,corresponding author570,571 B. Jenni-Moser,corresponding author572 M.-M. Jeitziner,572 M. S. Galassi,corresponding author573 F. L. Sales,573 K. C. L. de Moraes,573 C. L. Batista,573 J. A. de Souza J?nior,573 T. B. Marcari,573 R. Lobato,573 C. S. A. A. Castro,573 L. M. de Souza,573 F. F. P. Rodrigues,573 N. G. Correa,573 A. M. Pelegrini,573 R. A. C. Eid,573 K. T. Timenetsky,573 D. Cazati,574 M. Lobato,corresponding author575 P. S. Diniz,575 L. L. Rocha,575 A. M. Cavalheiro,575 N. M. Lucinio,575 E. R. Santos,575 M. Norrenberg,corresponding author576 A. Gleize,576 J. C. Preiser,576 I. Fernandez Simon,corresponding author577 S. Alcantara Carmona,577 I. Lipperheide Valhonrat,577 J. Palamidessi Dominguez,577 A. Naharro Abellan,577 P. Matia Almudevar,577 F. Davila,577 J. J. Rubio,577 A. J. Ramos,577 a. J. Roldan Reina,corresponding author578 N. Palomo Lopez,579 M. Adriaensens Perez,579 D. X. Cuenca Apolo,579 L. Martin Villen,579 F. M. Porras Lopez,579 I. Palacios Garcia,579 J. R. Naranjo Izurieta,579 J. J. Egea Guerrero,579 Renal Transplantation HUVR, S. Calvert,corresponding author580 M. Quint,580 K. Adeniji,580 R. Young,581 D. D. Shevill,corresponding author582 E. Robertson,582 P. Garside,583 E. Walter,583 P. Isotti,corresponding author584 M. M. De Vecchi,585 A. E. Perduca,585 A. Negro,585 G. Villa,585 D. F. Manara,585 L. Cabrini,585 A. Zangrillo,585 J. F. Frencken,corresponding author586,587 L. van Baal,586 L. M. Peelen,586,587 D. W. Donker,586 J. Horn,588 T. van der Poll,589,590,591 W. A. van Klei,592 M. J. M. Bonten,587,593 O. L. Cremer,586 C. E. Menard,corresponding author594 A. Kumar,595,596 E. Rimmer,597 S. Doucette,598 A. F. Turgeon,599,600 B. L. Houston,597 D. S. Houston,597 R. Zarychanski,595,597 B. Bollen Pinto,corresponding author601 M. Carrara,602 M. Ferrario,602 K. Bendjelid,601 J. Nunes,corresponding author603 P. Diaz,603 G. Silva,603 S. Escorcio,603 S. Chaves,603 M. Jardim,603 N. Fernandes,603 M. C?mara,603 R. Duarte,603 C. A. Pereira,603 J. Vieira,603 J. J. Nobrega,603 C. M. Coronado Robles,corresponding author604 M. A. Montes de Oca-Sandoval,604 A. Sanchez-Rodriguez,604 J. G. Joya-Galeana,604 A. Correa-Morales,604 G. Camarena-Alejo,604 J. Aguirre-Sanchez,604 J. Franco-Granillo,604 M. Soliman,corresponding author605 A. Al Azab,605 R. El Hossainy,605 H. Nagy,605 M. Nirmalan,606 I. A. Crippa,corresponding author607 F. Zama Cavicchi,607 J. L. Vincent,607 J. Creteur,607 F. S. Taccone,607 A. Chaari,corresponding author608 K. Abdel Hakim,609 H. Hassanein,609 M. Etman,609 M. El Bahr,609 K. Bousselmi,609 E. S. Khalil,609 V. Kauts,609 W. F. Casey,609 H. Imahase,corresponding author610 Y. Sakamoto,610 S. Inoue,610 K. C. Yamada,610 H. Koami,610 T. Miike,610 F. Nagashima,610 T. Iwamura,610 A. Boscolo,corresponding author611 V. Lucchetta,611 E. Piasentini,611 D. Bertini,611 L. Manesso,611 L. Spiezia,612 P. Simioni,612 C. Ori,613 R. B. Souza,corresponding author614 A. M. Martins,615 A. M. A. Liberatore,616 Y. R. Kang,616 M. N. Nakamae,616 J. C. F. Vieira,616 I. H. J. Koh,616 K. Hanslin,corresponding author617 F. Wilske,618 P. Skorup,618 J. Sjolin,618 M. Lipcsey,617 W. Jin Long,corresponding author619 C. Er Zhen,619 A. Vakalos,corresponding author620 V. Avramidis,620 S. H. Wu,corresponding author621 L. J. Shyu,622 C. H. Li,621 C. H. Yu,621 H. C. Chen,623 C. H. Wang,621 K. H. Lin,621 Z. E. Aray,corresponding author624 C. F. Gomez,624 A. P. Tejero,624 D. D. Monge,624 V. M. Losada,624 C. M. Tarancon,624 S. D. Cortes,624 A. M. Gutierrez,624 T. P. alvarez,624 A. Rouze,corresponding author625 K. Jaffal,625 S. Six,625 K. Stolz,625 V. Cattoen,625 S. Nseir,625 J. M. Arnal,corresponding author626,627 M. Saoli,626 D. Novotni,627 A. Garnero,626 T. Becher,corresponding author628 V. Buchholz,628 D. Sch?dler,628 I. Frerichs,628 N. Weiler,628 N. Eronia,corresponding author629 T. Mauri,630 S. Gatti,629 E. Maffezzini,631 A. Bronco,631 L. Alban,630 T. Sasso,630 C. Marenghi,630 G. Grasselli,630 A. Pesenti,630 G. Bellani,629,631 A. Al-Fares,corresponding author632 L. Del Sorbo,633 S. Anwar,633 F. Facchin,633 S. Azad,634 R. Zamel,634 N. Ferguson,633 M. Cypel,634 S. Keshavjee,634 E. Fan,633 E. Durlinger,corresponding author635 A. Spoelstra-de Man,635 B. Smit,635 H. J. de Grooth,635 A. Girbes,635 H. Oudemans-van Straaten,635 Y. Smulders,636 M. A. Alfaro,corresponding author637 F. Parrilla,637 A. Meli,638 M. Pellegrini,638 N. Rodriguez,637 J. M. Goyeneche,637 I. Moran,637 H. Aguirre,637 J. Mancebo,637 S. J. H. Heines,corresponding author639 U. Strauch,639 D. C. J. J. Bergmans,639 P. Blankman,corresponding author640 A. Shono,640 D. Hasan,640 D. Gommers,640 W. Y. Chung,corresponding author641 K. S. Lee,641 Y. J. Jung,641 J. H. Park,642 S. S. Sheen,641 K. J. Park,641 R. Worral,corresponding author643 S. Denham,643 P. Isherwood,643 S. E. Rees,corresponding author644 S. Larraza,644 N. Dey,645 S. Spadaro,646 J. B. Brohus,647 R. W. Winding,645 C. A. Volta,646 D. S. Karbing,644 F. Ampatzidou,corresponding author648 A. Vlachou,649 G. Kehagioglou,649 T. Karaiskos,649 A. Madesis,649 C. Mauromanolis,649 N. Michail,649 G. Drossos,649 N. Saraj,650 S. Rijkenberg,corresponding author650 H. M. Feijen,650 H. Endeman,650 A. A. J. Donnelly,corresponding author651 E. Morgan,651 H. Garrard,651 H. Buckley,651 L. Russell,corresponding author652,653 N. Haase,652,653 A. Perner,652 C. Goh,corresponding author654,655 K. Mouyis,654 C. L. N. Woodward,656 J. Halliday,654 G. B. Encina,corresponding author657 J. Ros,658 L. Lagunes,657 J. Tabernero,659 F. Bosch,660 J. Rello,661 D. Garcia Huertas,corresponding author662 F. Manzano,662 E. Morente-Constantin,662 B. Rivera-Gines,662 M. Colmenero-Ruiz,662 A. Naharro Abellan,corresponding author663 L. Perez Perez,663 A. Perez Lucendo,663 P. Matia Almudevar,663 J. Palamidessi Dominguez,663 P. Rodriguez Villamizar,663 J. Garcia Sanz,663 I. Fernandez Simon,663 B. Lobo Valbuena,663 S. Alcantara Carmona,663 M. Pais,corresponding author664 S. Ramalingam,664 C. Diaz,corresponding author665 L. Fox,666 M. Santafe,665 P. Barba,666 M. Garcia,665 S. Leal,665 M. Perez,665 M. L. Perez Perez,corresponding author667 A. Naharro Abellan,667 A. Perez Lucendo,667 P. Matia Almudevar,667 J. Palamidessi Dominguez,667 P. Rodriguez Villamizar,667 J. Veganzones,667 I. Fernandez Simon,667 B. Lobo Valbuena,667 N. Martinez,668 S. Alcantara Carmona,667 I. Moors,corresponding author669 D. Mokart,670 F. P?ne,671 J. Lambert,672 A. Kouatchet,673 J. Mayaux,674 F. Vincent,675 M. Nyunga,676 F. Bruneel,677 L. Laisne,672 A. Rabbat,671 C. Lebert,678 P. Perez,679 M. Chaize,672 A. Renault,680 A. P. Meert,681 R. Hamidfar,682 M. Jourdain,683 M. Darmon,672 B. Schlemmer,672 S. Chevret,684 V. Lemiale,672 E. Azoulay,672 D. Benoit,685 D. Martins-Branco,corresponding author686 M. Sousa,687 S. Marum,687 M. J. Bouw,687 G. Galstyan,corresponding author688 P. Makarova,688 E. Parovichnikova,689 L. Kuzmina,690 V. Troitskaya,689 N. Drize,691 E. Gemdzhian,692 V. Savchenko,693 H. C. Chao,corresponding author694 E. Kılıc,corresponding author695 B. Demiriz,696 M. L. Uygur,695 M. S?r?c?,695 K. Cınar,697 A. E. Yıldırım,698 K. Kiss,corresponding author699 B. Koves,700 V. Csernus,701 Z. Molnar,699 A. Ntantana,corresponding author702 D. Matamis,702 S. Savvidou,702 M. Giannakou,703 M. Gouva,704 G. Nakos,705 V. Koulouras,705 S. Gaffney,corresponding author706 E. Black,706 R. Docking,706 C. Judge,707 T. Drew,corresponding author708 H. Misran,708 R. Munshi,709 L. McGovern,708 M. Coyle,708 L. Dunne,708 E. Deasy,709,710 P. Lavin,707 A. Fahy,708 D. M. Darcy,709 M. Donnelly,708 N. H. Ismail,corresponding author711 T. Hall,corresponding author712 K. Wykes,712 J. Jack,712 W. C. Ngu,712 P. Morgan,712 J. Ruiz-Ramos,714 P. Ramirez,corresponding author714 M. Gordon,714 E. Villarreal,714 J. Frasquet,715 J. L. Poveda-Andres,716 A. Castellanos,714 C. E. Ijssennagger,corresponding author717 S. ten Hoorn,717 A. van Wijk,717 J. M. van den Broek,718 P. R. Tuinman,717 A. M. Elmenshawy,corresponding author719 B. D. Hammond,corresponding author720 G. Gibbon,721 T. Belcham,721 K. Burton,721 L. U. Taniguchi,corresponding author722,723 F. J. S. Ramos,724 A. K. Momma,724 A. P. R. Martins-Filho,724 J. J. Bartocci,724 M. F. D. Lopes,724 M. H. Sad,724 C. M. Rodrigues,724 E. M. C. Pires,724 J. M. Vieira, Jr,724 M. A. Leite,corresponding author725 L. D. Murbach,725 E. F. Osaku,725 J. Barreto,725 S. T. Duarte,725 S. Taba,725 D. Miglioranza,725 D. P. Gund,725 C. F. Lordani,725 C. R. L. M. Costa,725 S. M. Ogasawara,725 A. C. Jorge,725 P. A. D. Duarte,725 S. Spadaro,corresponding author726 M. Capuzzo,726 F. Dalla Corte,726 S. Terranova,726 G. Scaramuzzo,726 A. Fogagnolo,726 S. Bertacchini,726 A. Bellonzi,726 R. Ragazzi,726 C. A. Volta,726 C. Cruz,corresponding author727 A. Nunes,727 F. Seabra Pereira,727 I. Arag?o,727 A. F. Cardoso,727 C. Santos,727 M. J. Malheiro,727 H. Castro,727 T. Cardoso,727 J. Paratz,corresponding author728,729 J. Kenardy,728 T. Comans,729 F. Coyer,730 P. Thomas,731 R. Boots,728 N. Pereira,corresponding author732 A. Vilas-Boas,732 E. Gomes,732 C. Dias,732 J.

Publish date

2016 Sep 29

PMID

25316710

Abstract

SRC homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) is a cytosolic adaptor protein that plays an important role in the T-cell receptor-mediated T-cell signaling pathway. SLP-76 links proximal receptor stimulation to downstream effectors through interaction with many signaling proteins. Previous studies showed that mutation of three tyrosine residues, Tyr112, Tyr128, and Tyr145, in the N terminus of SLP-76 results in severely impaired phosphorylation and activation of Itk and PLCγ1, which leads to defective calcium mobilization, Erk activation, and NFAT activation. To expand our knowledge of the role of N-terminal phosphorylation of SLP-76 from these three tyrosine sites, we characterized nearly 1000 tyrosine phosphorylation sites via mass spectrometry in SLP-76 reconstituted wild-type cells and SLP-76 mutant cells in which three tyrosine residues were replaced with phenylalanines (Y3F mutant). Mutation of the three N-terminal tyrosine residues of SLP-76 phenocopied SLP-76-deficient cells for the majority of tyrosine phosphorylation sites observed, including feedback on proximal T-cell receptor signaling proteins. Meanwhile, reversed phosphorylation changes were observed on Tyr192 of Lck when we compared mutants to the complete removal of SLP-76. In addition, N-terminal tyrosine sites of SLP-76 also perturbed phosphorylation of Tyr440 of Fyn, Tyr702 of PLCγ1, Tyr204, Tyr397, and Tyr69 of ZAP-70, revealing new modes of regulation on these sites. All these findings confirmed the central role of N-terminal tyrosine sites of SLP-76 in the pathway and also shed light on novel signaling events that are uniquely regulated by SLP-76 N-terminal tyrosine residues.

Signaling events induced by the T-cell receptor (TCR)1 play an essential role in the adaptive immune response, important for T-cell proliferation, differentiation, and cytokine secretion. TCR engagement results in sequential activation of Src kinase Lck and Fyn, which phosphorylates the CD3ζ-chain immunoreceptor tyrosine-based activation motifs (ITAMs) (1). Phosphorylated ITAMs recruit and activate the Syk family protein kinase ZAP-70, which phosphorylates the transmembrane scaffold linker for activation of T cells (2), as well as SH2 domain-containing leukocyte protein of 76 kDa (SLP-76) (3), forming a signalosome complex essential for the assembly of downstream signaling proteins.

SLP-76, as an adaptor protein, lacks intrinsic enzymatic function but serves as an essential protein scaffold, recruiting other proteins for correct localization during T-cell signaling. Studies with SLP-76-deficient mice and SLP-76-deficient T-cell lines revealed a very profound role for SLP-76 in T-cell development and activation (4-7). In SLP-76-deficient Jurkat T cells, defects were observed in phosphorylation and activation of PLCγ1, calcium mobilization, Erk activation, and cytokine gene transcription following TCR ligation (6). SLP-76 consists of three domains: an N-terminal acidic region containing three tyrosine residues, Tyr112, Tyr128, and Tyr145; a central proline-rich region; and a C-terminal SH2 domain (7). Upon TCR activation, SLP-76 is recruited to the linker for activation of T cells signaling complex through binding with GADS (8), nucleating the interaction of signaling proteins, including PLCγ1, Itk, Vav, Nck, and adhesion and degranulation adaptor protein (9). PLCγ1 is recruited to the SLP-76 signaling complex through binding to both LAT and SLP-76. Phosphorylated Tyr145 of SLP-76 is recognized by the SH2 domain of the Tec family kinase Itk, which also binds to the proline-rich domain of SLP-76 (10). This interaction maintains Itk in an active conformation (7). The binding of PLCγ and active Itk to SLP-76 leads to the phosphorylation and activation of PLCγ1 and subsequent generation of the second messengers inositol 1,4,5-trisphosphate and diacylglcycerol (11). SLP-76 also regulates cytoskeletal rearrangement through the assembly of a tri-molecular signaling complex with Vav and Nck (12). In addition, the interaction between the tyrosine-phosphorylated adaptor protein and the SH2 domain of SLP-76 regulates integrin activation (13).

Besides its importance in regulating downstream signaling proteins, we recently revealed that SLP-76 plays an important role in mediating upstream signaling proteins (14). In a phosphoproteomic study examining cells deficient in SLP-76, SLP-76 was required for mediation of the phosphorylation of PAG (14), which transmits negative regulatory signals in complex with Csk (15). In addition, this earlier study revealed that the absence of SLP-76 perturbs the phosphorylation of Lck and, subsequently, a large number of Lck-regulated signaling molecules (i.e. CD3ε, -δ, -γ, and -ζ chains; ZAP-70) (14). These findings led to the hypothesis that SLP-76 mediates both PAG negative feedback and ERK positive feedback of Lck (14).

Phosphorylation of three N-terminal tyrosine residues is essential for the function of SLP-76 (16). Upon phosphorylation by ZAP-70, phosphorylated Tyr112 and Tyr128 bind to SH2 domains of Vav (17-20), Nck (12, 21), and the p85 subunit of phosphatidylinositol 3-kinase (22), whereas phosphorylated Tyr145 is recognized by the SH2 domain of Itk (10). N-terminal tyrosines of SLP-76 are required for the TCR-induced phosphorylation and activation of Itk and PLCγ1 (7).

However, the current understanding of N-terminal tyrosines of SLP-76 is incomplete, especially regarding their role in the newly discovered feedback regulation of the phosphorylation of upstream signaling proteins. For further elucidation of the function of SLP-76 N-terminal tyrosines in the regulation of the TCR signaling pathway, a wide-scale view of temporal changes in TCR signaling components is required. Quantitative mass-spectrometry-based phosphoproteomics is a powerful way to achieve this goal by enabling the system-wide identification of sites on proteins phosphorylated in the T cell, as well as the quantification of protein phosphorylation (14, 23-28). In this study, a wide-scale quantitative phosphoproteomic method was used to identify TCR-responsive tyrosine phosphorylation sites and to gain system-wide insight into the role of N-terminal tyrosine residues of SLP-76 in the TCR signaling pathway.

Title

SRC Homology 2 Domain-containing Leukocyte Phosphoprotein of 76 kDa (SLP-76) N-terminal Tyrosine Residues Regulate a Dynamic Signaling Equilibrium Involving Feedback of Proximal T-cell Receptor (TCR) Signaling*

Author

Qinqin Ji,‡ Yiyuan Ding,‡ and Arthur R. Salomon‡§¶

Publish date

2015 Jan;

PMID

30965610

Abstract

Quorum sensing (QS) is a cell-to-cell communication system that uses autoinducers as signaling molecules to enable inter-species and intra-species interactions in response to external stimuli according to the population density. QS allows bacteria such as Acinetobacter baumannii to react rapidly in response to environmental changes and hence, increase the chances of survival. A. baumannii is one of the causative agents in hospital-acquired infections and the number of cases has increased remarkably in the past decade. In this study, A. baumannii strain 863, a multidrug-resistant pathogen, was found to exhibit QS activity by producing N-acyl homoserine lactone. We identified the autoinducer synthase gene, which we named abaI, by performing whole genome sequencing analysis of A. baumannii strain 863. Using high resolution tandem triple quadrupole mass spectrometry, we reported that abaI of A. baumannii strain 863 produced 3-hydroxy-dodecanoyl-homoserine lactone. A gene deletion mutant was constructed, which confirmed the functionality of abaI. A growth defect was observed in the QS-deficient mutant strain. Transcriptome profiling was performed to determine the possible genes regulated by QS. Four groups of genes that showed differential expression were discovered, namely those involved in carbon source metabolism, energy production, stress response and the translation process.

KEYWORDS

Acinetobacter baumannii, quorum sensing, transcriptomic, RNA-Seq, recombineering, mutagenesis

Title

Characterization and Transcriptome Studies of Autoinducer Synthase Gene from Multidrug Resistant Acinetobacter baumannii Strain 863

Author

Chung-Kiat Ng,1 Kah-Yan How,2 Kok-Keng Tee,1 and Kok-Gan Chan2,3,*

Publish date

2019 Apr;