0 1 A a DT 2 8 direct direct JJ 9 20 interaction interaction NN 21 28 between between IN 29 32 the the DT 33 40 adaptor adaptor NN 41 48 protein protein NN 49 54 Cbl-b Cbl-b NNP 55 58 and and CC 59 62 the the DT 63 69 kinase kinase NNP 70 76 zap-70 zap-70 NN 77 84 induces induce VBZ 85 86 a a DT 87 95 positive positive JJ 96 102 signal signal NN 103 105 in in IN 106 107 T t NN 108 113 cells cell NNS 113 114 . . . 116 126 Engagement engagement NN 127 129 of of IN 130 133 the the DT 134 140 T-cell t-cell NN 141 149 receptor receptor NN 150 151 ( ( ( 151 159 TCR)-CD3 tcr)-cd3 NN 160 167 complex complex NN 168 175 induces induce VBZ 176 177 a a DT 178 183 rapid rapid JJ 184 192 increase increase NN 193 195 in in IN 196 199 the the DT 200 210 activities activity NNS 211 213 of of IN 214 224 Src-family Src-family NNP 225 228 and and CC 229 246 Syk/Zap-70-family Syk/Zap-70-family NNP 247 254 kinases kinase NNS 255 256 [ [ ( 256 257 1 1 CD 257 258 ] ] ) 259 260 [ [ ( 260 261 2 2 CD 261 262 ] ] ) 262 263 . . . 264 269 These these DT 270 279 activated activate VBN 280 287 kinases kinase NNS 288 292 then then RB 293 299 induce induce VBP 300 303 the the DT 304 312 tyrosine tyrosine NN 313 328 phosphorylation phosphorylation NN 329 331 of of IN 332 340 multiple multiple JJ 341 354 intracellular intracellular JJ 355 363 proteins protein NNS 363 364 , , , 365 375 eventually eventually RB 376 383 leading lead VBG 384 386 to to TO 387 393 T-cell t-cell NN 394 404 activation activation NN 404 405 . . . 406 409 One one CD 410 412 of of IN 413 416 the the DT 417 426 prominent prominent JJ 427 437 substrates substrate NNS 438 441 for for IN 442 447 these these DT 448 455 kinases kinase NNS 456 458 is be VBZ 459 462 the the DT 463 470 adaptor adaptor NN 471 478 protein protein NN 479 482 Cbl Cbl NNP 483 484 [ [ ( 484 485 3 3 CD 485 486 ] ] ) 487 490 and and CC 491 497 recent recent JJ 498 505 studies study NNS 506 513 suggest suggest VBP 514 518 that that IN 519 522 Cbl Cbl NNP 523 533 negatively negatively RB 534 543 regulates regulate VBZ 544 552 upstream upstream JJ 553 560 kinases kinase NNS 561 565 such such JJ 566 568 as as IN 569 572 Syk Syk NNP 573 576 and and CC 577 583 Zap-70 Zap-70 NNP 584 585 [ [ ( 585 586 4 4 CD 586 587 ] ] ) 588 589 [ [ ( 589 590 5 5 CD 590 591 ] ] ) 591 592 . . . 593 598 Cbl-b Cbl-b NNP 598 599 , , , 600 601 a a DT 602 611 homologue homologue NN 612 614 of of IN 615 618 Cbl Cbl NNP 618 619 , , , 620 622 is be VBZ 623 629 widely widely RB 630 639 expressed express VBN 640 642 in in IN 643 647 many many JJ 648 655 tissues tissue NNS 656 659 and and CC 660 665 cells cell NNS 666 675 including include VBG 676 689 hematopoietic hematopoietic JJ 690 695 cells cell NNS 696 697 [ [ ( 697 698 6 6 CD 698 699 ] ] ) 700 701 [ [ ( 701 702 7 7 CD 702 703 ] ] ) 703 704 . . . 705 710 Cbl-b Cbl-b NNP 711 720 undergoes undergo VBZ 721 726 rapid rapid JJ 727 735 tyrosine tyrosine NN 736 751 phosphorylation phosphorylation NN 752 756 upon upon IN 757 768 stimulation stimulation NN 769 771 of of IN 772 775 the the DT 776 779 TCR TCR NNP 780 783 and and CC 784 792 cytokine cytokine NN 793 802 receptors receptor NNS 803 804 [ [ ( 804 805 8 8 CD 805 806 ] ] ) 807 808 [ [ ( 808 809 9 9 CD 809 810 ] ] ) 810 811 . . . 812 815 The the DT 816 820 role role NN 821 823 of of IN 824 829 Cbl-b Cbl-b NNP 830 832 is be VBZ 833 840 unclear unclear JJ 840 841 , , , 842 849 however however RB 849 850 . . . 851 855 Here here RB 855 856 , , , 857 859 we we PRP 860 864 show show VBP 865 869 that that IN 870 884 overexpression overexpression NN 885 887 of of IN 888 893 Cbl-b Cbl-b NNP 894 896 in in IN 897 898 T t NN 899 904 cells cell NNS 905 912 induced induce VBD 913 916 the the DT 917 929 constitutive constitutive JJ 930 940 activation activation NN 941 943 of of IN 944 947 the the DT 948 961 transcription transcription NN 962 968 factor factor NN 969 976 nuclear nuclear JJ 977 983 factor factor NN 984 986 of of IN 987 996 activated activate VBN 997 998 T t NN 999 1004 cells cell NNS 1005 1006 ( ( ( 1006 1010 NFAT NFAT NNP 1010 1011 ) ) ) 1011 1012 . . . 1013 1014 A a DT 1015 1031 loss-of-function loss-of-function JJ 1032 1040 mutation mutation NN 1041 1043 in in IN 1044 1049 Cbl-b Cbl-b NNP 1050 1059 disrupted disrupt VBD 1060 1063 the the DT 1064 1075 interaction interaction NN 1076 1083 between between IN 1084 1089 Cbl-b Cbl-b NNP 1090 1093 and and CC 1094 1100 Zap-70 Zap-70 NNP 1101 1104 and and CC 1105 1111 nearly nearly RB 1112 1122 completely completely RB 1123 1132 abrogated abrogate VBD 1133 1136 the the DT 1137 1151 Cbl-b-mediated cbl-b-mediated JJ 1152 1162 activation activation NN 1163 1165 of of IN 1166 1170 NFAT NFAT NNP 1170 1171 . . . 1172 1178 Unlike unlike IN 1179 1182 the the DT 1183 1191 proposed propose VBN 1192 1196 role role NN 1197 1199 of of IN 1200 1203 Cbl Cbl NNP 1204 1206 as as IN 1207 1208 a a DT 1209 1217 negative negative JJ 1218 1227 regulator regulator NN 1227 1228 , , , 1229 1232 our our PRP$ 1233 1240 results result NNS 1241 1248 suggest suggest VBP 1249 1253 that that IN 1254 1257 the the DT 1258 1261 Cbl Cbl NNP 1262 1271 homologue homologue NN 1272 1277 Cbl-b Cbl-b NNP 1278 1281 has have VBZ 1282 1283 a a DT 1284 1292 positive positive JJ 1293 1297 role role NN 1298 1300 in in IN 1301 1307 T-cell T-cell NNP 1308 1317 signaling signaling NN 1317 1318 , , , 1319 1323 most most RBS 1324 1330 likely likely JJ 1331 1334 via via IN 1335 1336 a a DT 1337 1343 direct direct JJ 1344 1355 interaction interaction NN 1356 1360 with with IN 1361 1364 the the DT 1365 1373 upstream upstream JJ 1374 1380 kinase kinase NNP 1381 1387 Zap-70 Zap-70 NNP 1387 1388 . . .