0 13 Costimulation costimulation NN 14 25 requirement requirement NN 26 29 for for IN 30 34 AP-1 AP-1 NNP 35 38 and and CC 39 47 NF-kappa NF-kappa NNP 48 49 B B NNP 50 63 transcription transcription NN 64 70 factor factor NN 71 81 activation activation NN 82 84 in in IN 85 86 T t NN 87 92 cells cell NNS 92 93 . . . 95 98 The the DT 99 114 transcriptional transcriptional JJ 115 123 activity activity NN 124 126 of of IN 127 130 the the DT 131 135 IL-2 il-2 NN 136 144 promoter promoter NN 145 153 requires require VBZ 154 160 T-cell t-cell NN 161 174 costimulation costimulation NN 175 184 delivered deliver VBN 185 187 by by IN 188 191 the the DT 192 195 TCR TCR NNP 196 199 and and CC 200 203 the the DT 204 213 auxiliary auxiliary JJ 214 222 receptor receptor NN 223 227 CD28 cd28 NN 227 228 . . . 229 236 Several several JJ 237 250 transcription transcription NN 251 258 factors factor NNS 259 270 participate participate VBP 271 273 in in IN 274 278 IL-2 il-2 NN 279 287 promoter promoter NN 288 298 activation activation NN 298 299 , , , 300 305 among among IN 306 311 which which WDT 312 315 are be VBP 316 325 AP-1-like ap-1-like JJ 326 333 factors factor NNS 334 337 and and CC 338 346 NF-kappa NF-kappa NNP 347 349 B. B. NNP 350 357 Protein Protein NNP 358 373 phosphorylation phosphorylation NN 374 377 has have VBZ 378 380 an an DT 381 390 important important JJ 391 395 role role NN 396 398 in in IN 399 402 the the DT 403 413 regulation regulation NN 414 416 of of IN 417 422 these these DT 423 426 two two CD 427 434 factors factor NNS 434 435 : : : 436 437 ( ( ( 437 438 1 1 LS 438 439 ) ) ) 440 442 it it PRP 443 450 induces induce VBZ 451 454 the the DT 455 470 transactivating transactivate VBG 471 479 capacity capacity NN 480 482 of of IN 483 486 the the DT 487 491 AP-1 ap-1 NN 492 499 protein protein NN 500 505 c-Jun c-jun NN 505 506 ; ; : 507 510 and and CC 511 512 ( ( ( 512 513 2 2 LS 513 514 ) ) ) 515 517 it it PRP 518 520 is be VBZ 521 529 involved involve VBN 530 532 in in IN 533 536 the the DT 537 544 release release NN 545 547 of of IN 548 551 the the DT 552 563 cytoplasmic cytoplasmic JJ 564 573 inhibitor inhibitor NN 573 574 , , , 575 576 I i NN 577 582 kappa kappa NN 583 584 B B NNP 584 585 , , , 586 590 from from IN 591 599 NF-kappa NF-kappa NNP 600 601 B B NNP 601 602 , , , 603 611 allowing allow VBG 612 625 translocation translocation NN 626 628 of of IN 629 632 the the DT 633 639 latter latter JJ 640 644 into into IN 645 648 the the DT 649 656 nucleus nucleus NN 656 657 . . . 658 660 We we PRP 661 665 have have VBP 666 674 recently recently RB 675 680 shown show VBN 681 685 that that IN 686 690 both both CC 691 706 phosphorylation phosphorylation NN 707 716 processes process NNS 717 724 require require VBP 725 731 T-cell t-cell NN 732 745 costimulation costimulation NN 745 746 . . . 747 758 Furthermore furthermore RB 758 759 , , , 760 762 in in IN 763 772 activated activate VBN 773 774 T t NN 775 780 cells cell NNS 780 781 , , , 782 785 the the DT 786 794 kinetics kinetic NNS 795 797 of of IN 798 801 the the DT 802 805 two two CD 806 821 phosphorylation phosphorylation NN 822 828 events event NNS 829 832 are be VBP 833 844 essentially essentially RB 845 852 similar similar JJ 852 853 . . . 854 863 According accord VBG 864 866 to to TO 867 870 our our PRP$ 871 878 results result NNS 878 879 , , , 880 887 however however RB 887 888 , , , 889 892 the the DT 893 900 kinases kinase NNS 901 912 responsible responsible JJ 913 916 for for IN 917 920 the the DT 921 924 two two CD 925 934 processes process NNS 935 938 are be VBP 939 947 distinct distinct JJ 948 956 entities entity NNS 956 957 . . . 958 965 Whereas whereas IN 966 970 TPCK TPCK NNP 971 979 inhibits inhibit VBZ 980 995 phosphorylation phosphorylation NN 996 998 of of IN 999 1000 I i NN 1001 1006 kappa kappa NN 1007 1008 B B NNP 1009 1012 and and CC 1012 1013 , , , 1014 1026 consequently consequently RB 1026 1027 , , , 1028 1038 activation activation NN 1039 1041 of of IN 1042 1050 NF-kappa NF-kappa NNP 1051 1052 B B NNP 1052 1053 , , , 1054 1056 it it PRP 1057 1065 markedly markedly RB 1066 1074 enhances enhance VBZ 1075 1078 the the DT 1079 1087 activity activity NN 1088 1090 of of IN 1091 1094 JNK JNK NNP 1094 1095 , , , 1096 1099 the the DT 1100 1103 MAP MAP NNP 1104 1118 kinase-related kinase-related JJ 1119 1125 kinase kinase NNP 1126 1130 that that WDT 1131 1145 phosphorylates phosphorylate VBZ 1146 1149 the the DT 1150 1165 transactivation transactivation NN 1166 1172 domain domain NN 1173 1175 of of IN 1176 1181 c-Jun c-jun NN 1181 1182 . . . 1183 1185 We we PRP 1185 1186 , , , 1187 1196 therefore therefore RB 1196 1197 , , , 1198 1205 propose propose VBP 1206 1209 the the DT 1210 1220 activation activation NN 1221 1227 scheme scheme NN 1228 1237 presented present VBN 1238 1240 in in IN 1241 1247 FIGURE FIGURE NNP 1248 1249 3 3 CD 1250 1253 for for IN 1254 1260 T-cell t-cell NN 1261 1274 costimulation costimulation NN 1274 1275 . . . 1276 1289 Costimulation costimulation NN 1290 1297 results result VBZ 1298 1300 in in IN 1301 1304 the the DT 1305 1315 activation activation NN 1316 1318 of of IN 1319 1320 a a DT 1321 1330 signaling signaling NN 1331 1338 pathway pathway NN 1339 1343 that that WDT 1344 1349 leads lead VBZ 1350 1352 to to TO 1353 1356 the the DT 1357 1369 simultaneous simultaneous JJ 1370 1379 induction induction NN 1380 1382 of of IN 1383 1386 the the DT 1387 1390 two two CD 1391 1404 transcription transcription NN 1405 1412 factors factor NNS 1412 1413 , , , 1414 1418 AP-1 AP-1 NNP 1419 1422 and and CC 1423 1431 NF-kappa NF-kappa NNP 1432 1434 B. B. NNP 1435 1446 Integration Integration NNP 1447 1449 of of IN 1450 1453 the the DT 1454 1461 signals signal NNS 1462 1471 generated generate VBN 1472 1474 by by IN 1475 1478 TCR TCR NNP 1479 1482 and and CC 1483 1487 CD28 cd28 NN 1488 1498 engagement engagement NN 1499 1505 occurs occur VBZ 1506 1511 along along IN 1512 1516 this this DT 1517 1524 pathway pathway NN 1524 1525 , , , 1526 1531 which which WDT 1532 1536 then then RB 1537 1547 bifurcates bifurcate VBZ 1548 1550 to to TO 1551 1557 induce induce VB 1558 1559 I i NN 1560 1565 kappa kappa NN 1566 1567 B B NNP 1568 1583 phosphorylation phosphorylation NN 1584 1587 and and CC 1588 1596 NF-kappa NF-kappa NNP 1597 1598 B B NNP 1599 1609 activation activation NN 1610 1612 on on IN 1613 1616 the the DT 1617 1620 one one CD 1621 1625 hand hand NN 1625 1626 , , , 1627 1630 and and CC 1631 1634 JNK JNK NNP 1635 1645 activation activation NN 1646 1649 and and CC 1650 1655 c-Jun c-jun NN 1656 1671 phosphorylation phosphorylation NN 1672 1674 on on IN 1675 1678 the the DT 1679 1684 other other JJ 1684 1685 . . . 1686 1688 We we PRP 1689 1692 are be VBP 1693 1702 currently currently RB 1703 1710 engaged engage VBN 1711 1713 in in IN 1714 1722 defining define VBG 1723 1728 where where WRB 1729 1732 the the DT 1733 1736 two two CD 1737 1744 signals signal NNS 1745 1754 integrate integrate VBP 1755 1760 along along IN 1761 1764 the the DT 1765 1778 AP-1/NF-kappa AP-1/NF-kappa NNP 1779 1780 B B NNP 1781 1788 pathway pathway NN 1788 1789 . . .