0 7 Protein protein NN 8 14 kinase kinase NNP 15 16 C C NNP 17 20 and and CC 21 32 calcineurin calcineurin NN 33 42 synergize synergize VBP 43 45 to to TO 46 54 activate activate VB 55 62 IkappaB IkappaB NNP 63 69 kinase kinase NNP 70 73 and and CC 74 83 NF-kappaB NF-kappaB NNP 84 86 in in IN 87 88 T t NN 89 100 lymphocytes lymphocyte NNS 100 101 . . . 103 106 The the DT 107 114 nuclear nuclear JJ 115 121 factor factor NN 122 124 of of IN 125 131 kappaB kappaB NNP 132 133 ( ( ( 133 142 NF-kappaB NF-kappaB NNP 142 143 ) ) ) 144 146 is be VBZ 147 148 a a DT 149 159 ubiquitous ubiquitous JJ 160 173 transcription transcription NN 174 180 factor factor NN 181 185 that that WDT 186 188 is be VBZ 189 192 key key JJ 193 195 in in IN 196 199 the the DT 200 210 regulation regulation NN 211 213 of of IN 214 217 the the DT 218 224 immune immune JJ 225 233 response response NN 234 237 and and CC 238 250 inflammation inflammation NN 250 251 . . . 252 253 T t NN 254 258 cell cell NN 259 267 receptor receptor NN 268 269 ( ( ( 269 272 TCR TCR NNP 272 273 ) ) ) 274 287 cross-linking cross-linking NN 288 290 is be VBZ 291 293 in in IN 294 298 part part NN 299 307 required require VBN 308 311 for for IN 312 322 activation activation NN 323 325 of of IN 326 335 NF-kappaB NF-kappaB NNP 335 336 , , , 337 342 which which WDT 343 345 is be VBZ 346 355 dependent dependent JJ 356 358 on on IN 359 362 the the DT 363 378 phosphorylation phosphorylation NN 379 382 and and CC 383 394 degradation degradation NN 395 397 of of IN 398 410 IkappaBalpha IkappaBalpha NNP 410 411 . . . 412 414 By by IN 415 420 using use VBG 421 427 Jurkat Jurkat NNP 428 431 and and CC 432 439 primary primary JJ 440 445 human human JJ 446 447 T t NN 448 459 lymphocytes lymphocyte NNS 459 460 , , , 461 463 we we PRP 464 475 demonstrate demonstrate VBP 476 480 that that IN 481 484 the the DT 485 497 simultaneous simultaneous JJ 498 508 activation activation NN 509 511 of of IN 512 515 two two CD 516 522 second second JJ 523 533 messengers messenger NNS 534 536 of of IN 537 540 the the DT 541 554 TCR-initiated tcr-initiated JJ 555 561 signal signal NN 562 574 transduction transduction NN 574 575 , , , 576 583 protein protein NN 584 590 kinase kinase NNP 591 592 C C NNP 593 594 ( ( ( 594 597 PKC PKC NNP 597 598 ) ) ) 599 602 and and CC 603 614 calcineurin calcineurin NN 614 615 , , , 616 623 results result VBZ 624 626 in in IN 627 630 the the DT 631 642 synergistic synergistic JJ 643 653 activation activation NN 654 656 of of IN 657 660 the the DT 661 673 IkappaBalpha IkappaBalpha NNP 674 680 kinase kinase NNP 681 682 ( ( ( 682 685 IKK IKK NNP 685 686 ) ) ) 687 694 complex complex NN 695 698 but but CC 699 702 not not RB 703 705 of of IN 706 713 another another DT 714 722 putative putative JJ 723 735 IkappaBalpha IkappaBalpha NNP 736 742 kinase kinase NNP 742 743 , , , 744 752 p90(rsk) p90(rsk) NNP 752 753 . . . 754 756 We we PRP 757 761 also also RB 762 773 demonstrate demonstrate VBP 774 778 that that IN 779 782 the the DT 783 786 IKK IKK NNP 787 794 complex complex NN 794 795 , , , 796 799 but but CC 800 803 not not RB 804 812 p90(rsk) p90(rsk) NN 812 813 , , , 814 816 is be VBZ 817 828 responsible responsible JJ 829 832 for for IN 833 836 the the DT 837 839 in in FW 840 844 vivo vivo FW 845 860 phosphorylation phosphorylation NN 861 863 of of IN 864 876 IkappaBalpha IkappaBalpha NNP 877 885 mediated mediate VBN 886 888 by by IN 889 892 the the DT 893 906 co-activation co-activation NN 907 909 of of IN 910 913 PKC PKC NNP 914 917 and and CC 918 929 calcineurin calcineurin NN 929 930 . . . 931 935 Each each DT 936 942 second second JJ 943 952 messenger messenger NN 953 955 is be VBZ 956 965 necessary necessary JJ 965 966 , , , 967 969 as as IN 970 980 inhibition inhibition NN 981 983 of of IN 984 990 either either DT 991 994 one one NN 995 1003 reverses reverse VBZ 1004 1007 the the DT 1008 1018 activation activation NN 1019 1021 of of IN 1022 1025 the the DT 1026 1029 IKK IKK NNP 1030 1037 complex complex NN 1038 1041 and and CC 1042 1054 IkappaBalpha IkappaBalpha NNP 1055 1070 phosphorylation phosphorylation NN 1071 1073 in in FW 1074 1078 vivo vivo FW 1078 1079 . . . 1080 1094 Overexpression overexpression NN 1095 1097 of of IN 1098 1106 dominant dominant JJ 1107 1115 negative negative JJ 1116 1121 forms form NNS 1122 1124 of of IN 1125 1133 IKKalpha IKKalpha NNP 1134 1137 and and CC 1138 1143 -beta -beta NN 1144 1156 demonstrates demonstrate VBZ 1157 1161 that that IN 1162 1166 only only RB 1167 1174 IKKbeta IKKbeta NNP 1175 1177 is be VBZ 1178 1181 the the DT 1182 1188 target target NN 1189 1192 for for IN 1193 1196 PKC PKC NNP 1197 1200 and and CC 1201 1212 calcineurin calcineurin NN 1212 1213 . . . 1214 1219 These these DT 1220 1227 results result NNS 1228 1236 indicate indicate VBP 1237 1241 that that IN 1242 1248 within within IN 1249 1252 the the DT 1253 1260 TCR/CD3 tcr/cd3 NN 1261 1267 signal signal NN 1268 1280 transduction transduction NN 1281 1288 pathway pathway NN 1289 1293 both both CC 1294 1297 PKC PKC NNP 1298 1301 and and CC 1302 1313 calcineurin calcineurin NN 1314 1317 are be VBP 1318 1326 required require VBN 1327 1330 for for IN 1331 1334 the the DT 1335 1344 effective effective JJ 1345 1355 activation activation NN 1356 1358 of of IN 1359 1362 the the DT 1363 1366 IKK IKK NNP 1367 1374 complex complex NN 1375 1378 and and CC 1379 1388 NF-kappaB nf-kappab NN 1389 1391 in in IN 1392 1393 T t NN 1394 1405 lymphocytes lymphocyte NNS 1405 1406 . . .