JP 2008-260773 A 2008.10.30 (57)【要約】 【課題】新規なノッチリガンド
Contents
1. 29 J 2008 260773 A 2008 10 30 10 D D ooo 000 20 0 000 C 1000 0 0 Ju 0000 n n n n n 30 D D zb2. 10 20 30 27 JP 2008 260773 2008 10 30 1 2 LTC IC 16200 2500 150
3. JP 2008 260773 2008 10 30 10 10 20 30 40 l 000
4. Es NN E 10 20 30 40 50 JP 2008 260773 2008 10 30 25 10 20 30
5. 10 20 30 40 50 JP 2008 260773 2008 10 30 21 10 20
6. n 30 40 50
7. 10 20 30 40 50 JP 2008 260773 2008 10 30 12 10 20 30 40 50
8. 445000 23000 HDIEXIg 335000 16700 HD2EX I glX 418000 16000 HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 000 HHHHHHHHHHHHHHHHHHHHHHHH HHHHHHHHHHHHHHHHHH 0000 HHHHHHHHHHHHH 00000000 1 0000000 e000000000000 H ai m 2 42 z u Mr E HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH HHHHHHHHHHHHHHHHHHHHHHH JP 2008 260773 2008 10 30 28 10 20
9. 20 30 40 50 C
10. JP 2008 260773 2008 10 30 3
11. 50 7 JP 2008 260773 2008 10 30
12. JP 2008 260773 2008 10 30 13 10 20 30 40 50
13. 40 50 24 JP 2008 260773 2008 10 30 00u nnnn
14. JP 2008 260773 2008 10 30 18 l l C 10 H 20 100 C 30 40 50 C
15. C E 0 HHHHHHHHHH 1000 Ul 1000000000000 U 0100110000 u 0 1 00000 B D Ul U HHHHHHHHHHHH pet HHHHHHHHHHHH l B IU l 100000 000000 10 20 30 40 50
16. 14 JP 2008 260773 A 2008 10 30 10 20 30 40 50 JP 2008 260773 2008 10 30 15 10
17. 19 JP 2008 260773 A 2008 10 30
18. 10 20 30 40 50 JP 2008 260773 2008 10 30 17 10 C 20 C C 32 30 C C 32 40 50
19. IHHHHHHHH 0000 0000000 IHHHHHHHH 000000 0000 HH HHHHHHHH HH HH IHHHHH IHHHHH HHHHHHH IHHHHH Bun HHHHHHH IHHHHHHHH HHHHHHHHHHH 10 20 30 40 50 JP 2008 260773 2008 10 30 8 10 ly U 32 20 30 l
20. 30 40 50 JP 2008 260773 2008 10 30 22 10 20 30
21. D 50 o o o o Cv st s a oO oO oO E NA 3 3 um 3 o ES 3 3 C3 3 pic MET e um 3 3 o g 3 3 3 L3 _ E ES _ _ _ un Oo oOo Oo Oo oO oo oO r3 x E ES r3 Oo L3 O i 3 C3 3 r3 _ s r3 _ LI mm 3 C3 3 oO C Rat LJ LI oe um JP 2008 260773 2008 10 30 4
22. 40 50 JP 2008 260773 2008 10 30 9 10 n DU l l 20 30 40 50
23. 2008 260773 2008 10 30
24. 20 30 40 l 50 JP 2008 260773 2008 10 30 10 20 30 40
25. 50 l 2008 260773 2008 10 30
26. 40 C 50 JP 2008 260773 2008 10 30 23 10 C 20 30
27. EMI DNA CGGCGACGCC CGAGGGGATG GCGGCAGC 16 3 0 HEBR BUR DNA GAATTCCACC GCGGTGGAGC TCCAATTCGC 17 28 IDR HEB R SK 180 240 300 360 412 28 30 10 20 30 40 53 JP 2008 260773 2008 10 30 DN A TCAGCTGGGE GGCAAGCCCA CGGGGAAC 18 3 3 DN A GCGGCCGCTT ATCGATACCG TCGACCTCGA GGG 1 9 52 BK DNA TCATTTATCA TCATCATCTT TATAATCGCT GGGCGGCAAG CCCACGGGGA AC 20 36 S HOR BAK 28 33 52 10 20 30 40 54 JP 2008 260773 A 2008 10 30 DNA AAAGGATCCG AGGGCGGCAA GCCCACGGGG AACTC6 21
28. Ser Gly Val Phe Gln Leu Gln Leu Gin Glu Phe Ile Asn Glu Arg Gly 1 5 10 15 Val Leu Ala Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe 20 25 30 Arg Val Cys Leu Lys His Phe Ala Val Val Ser Pro Gly Pro Cys 35 40 45 Thr Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Ala 50 55 60 Val Arg Asp Asp Ser Ser Gly Gly Gly Arg Asn Pro Leu Gin Leu Pro 65 70 75 80 Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Ile Glu Ala Trp 85 90 95 His Ala Pro Gly Asp Asp Leu Arg Pro Glu Ala Leu Pro Pro Asp Ala 100 105 110 Leu le Ser Lys Ala Gln Gly Ser Leu Ala Vai Gly Gin Asn 115 120 125 Trp Leu Leu Asp Glu Gin Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser 130 185 140 Tyr Arg Val Ile Cys Ser Asp Asn Tyr Gly Asp ASn Cys Ser Arg 145 150 155 160 Leu Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gln Pro 185 170 175 Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln 180 185 190 Gln Pro Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser 10 20 30 40 35 JP 2008 260773 A 2008 10 30 195 200 205 Lys Pro Ala Glu Cys Leu Cys Arg Pro Gly Trp Gin Gly Arg Leu Cys 210 215 220 Asn Glu Cys Pro His Asn Gly Cys Arg His Gly Thr Cys Ser Thr 225 230 235 240 Pro Trp Gin Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp 245 250 255 Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Ala 260 265 210 Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys Arg P
29. 10 l 20 30 40 50 JP 2008 260773 2008 10 30 5 10
30. E 40 0 1000 D 1000 pH 1000 30 JP 2008 260773 A 2008 10 30 1 1 9 1 Gly Val Phe Leu Gln Leu Gln Glu Phe Asn Glu Arg Gly 1 5 10 15 Val Leu Ala Ser Gly Arg Pro Glu Pra Gly Cys Arg Thr Phe Phe 20 25 80 Arg Val Cys Leu Lys His Phe Ala Val Val Ser Pro Gly Pro Cys 39 40 45 Thr Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Ala 50 55 60 Val Arg Asp Asp Ser Ser Gly Gly Gly Arg Asn Pro Leu Gin Leu Pro 65 70 75 80 Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Ile Giu Ala Trp 85 90 95 His Ala Pro Gly Asp Asp Leu Arg Pro Glu Ala Leu Pro Pro Asp Ala 100 105 110 Leu le Ser Lys Ala Gln Gly Ser Leu Ala Val Gly Gin Asn 115 120 125 Trp Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser 130 195 140 Tyr Arg Val Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg 10 20 30 40 31 JP 2008 260773 2008 10 30 145 150 155 160 Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gin Pro 165 170 175 Asp Gly Asn Leu Ser Leu Pro Gly Trp Thr Gly Glu Tyr Cys 180 185 190 19
31. 2 500 Ser Gly Val Phe Gln Leu Leu Gln Glu Phe Ile Asn Glu Arg Gly 1 10 15 Val Leu Ala Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe 20 25 30 Arg Val Cys Leu Lys His Phe Gln Ala Val Val Ser Pro Gly Pro Cys 35 40 45 Thr Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Ala 50 55 60 Val Arg Asp Asp Ser Ser Gly Gly Gly Arg Asn Pro Leu Gln Leu Pro 65 10 15 80 Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Ile Giu Ala Trp 85 90 95 His Ala Pro Gly Asp Asp Leu Arg Pro Glu Ala Leu Pro Pro Asp Ala 100 105 110 10 20 30 40 32 JP 2008 260773 2008 10 30 Leu Ser Lys Ala Ile Gly Ser Leu Ala Val Gly Gin Asn 115 120 125 Trp Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser 130 135 140 Tyr Arg Val Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg 145 150 155 160 Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gin Pro 165 170 175 Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln 180 185 190 Gin Pro Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser 195 200 205 Lys Pro Ala Glu Cys Leu Cys Arg Pro Gly Trp Gin Gly Arg Leu Cys 210 215 220 Asn Glu Cys ie Pro His Asn Gly Cys Arg His Gly Thr Cys Ser Thr 225 230 230 240 Pro Trp Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp 245
32. 25 BA DNA TTATACCTCC GTGGCAATGA CACAT 22 52 DN A TCATTTATCA TCATCATCTT TATAATCTAC CTCCGTGGCA ATGACACATT 23 86 HOR DN A 36 20 02 10 20 30 40 55 JP 2008 260773 2008 10 30 AAGGATCCCG AGGGTGTCTG CTGGAAGCCA GGCTCA 36 24 38 BAR DN A CCTCTAGAGT CGC6GCCGTC GCACTCATTT ACC 33 HHHHHHHHH 20 2008 260773 2008 10 30 56 22 Www 90 ww eto 1 2 8560702 8461 9 1 Gi Mase L
33. Belg WHE 9 MIS 22 92 92 v2 SH c di 8 0 WD l ez 22120261 81 1 91 1 vL ELZL ILOLG 8 29 2 uije d 96 Sz 57 2008 260773 2008 10 30 8 5 1 1 amp 8 5 e e Q EH SE HD2EXlg a8 5 SS 10 0 58 2008 260773 2008 10 30 0000 HD1EXlg Counts 10 20 30 40 50 60 0 10 20 30 40 50 60 0 00000 2008260773000001
34. 546 594 642 690 138 186 834 882 10 20 30 40 39 JP 2008 260773 A 2008 10 30 165 170 115 GAT 660 AAC TTG TCC TGC CTG CCC GGT TGG ACT GGG GAA TAT TGC CAA Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln 180 185 190 CAG CCT ATC TGT CTT TCG GGC TGT CAT GAA CAG AAT GGC TAC TGC AGC Gin Pro Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser 195 200 205 AAG CCA GCA GAG TGC CTC TGC CGC CCA GGC CAG GGC CGG CTG TGT Lys Pro Ala Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys 210 215 220 AAC GAA TGC ATC CCC CAC AAT GGC CGC GGC ACC TGC AGC ACT Asn Glu Cys Ile Pro His Asn Gly Cys Arg His Gly Thr Cys Ser Thr 225 230 235 240 CCC TGG CAA TGT GAT GAG GGC TGG GGA GGC CTG TGT GAC Pro Trp Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp 245 250 255 CAA GAT CTC AAC TAC TGC ACC CAC CAC TCC CCA TGC AAG AAT GGG GCA Gin Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Ala 260 265 270 ACG TGC TCC AAC AGT GGG CAG CGA AGC TAC ACC TGC ACC TGT CGC CCA Thr Cys Ser Asn Ser Gly Arg Ser Tyr Thr Cys Thr Cys Arg Pro 215 280 285 GGC TAC ACT GGT GTG GAC TGT GAG CTG GAG CTC AGC GAG TGT GAC AGC Gly Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser 290 295 300 AAC CCC TGT CGC AAT GGA GGC TGT AAG GAC CAG GAG GAT GGC TAC Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp Gly Tyr 305 310 315 320 930 978 1026 1074 1122 11
35. C HH 6 40 50 MEET JP 2008 260773 2008 10 30
36. 256 306 354 402 450 10 20 30 40 38 JP 2008 260773 A 2008 10 30 Val Leu Ala Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe 20 25 30 CGC GTC TGC CTT AAG CAC TTC CAG GCG GTC GTC TCG CCC GGA CCC TGC Arg Val Cys Leu Lys His Phe Ala Val Val Ser Pro Gly Pro Cys 35 40 45 ACC TTC GGG ACC GTC TCC ACG CCG GTA TTG GGC ACC AAC TCC TTC GCT Thr Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Ala 50 55 60 GTC CGG GAC GAC AGT AGC GGC GGG GGG CGC CCT CTC CAA CTG CCC Val Arg Asp Asp Ser Ser Gly Gly Gly Arg Asn Pro Leu Gin Leu Pro 65 70 15 80 TTC AAT TTC ACC TGG CCG GGT ACC TTC TCG CTC ATC ATC GAA GCT TGG Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Ile Glu Ala Trp 85 90 95 CAC GCG CCA GGA GAC GAC CGG GAG GCC TTG CCA CCA GAT GCA His Ala Pro Gly Asp Asp Leu Arg Pro Glu Ala Leu Pro Pro Asp Ala 100 105 110 AGC AAG ATC GCC ATC CAG GGC GGT CAG AAC Leu Ser Lys Ile Ala Gln Gly Ser Leu Ala Val Gly Gin Asn 115 120 125 TGG TTA TTG GAT GAG CAA AGC ACC CTC ACA AGG CTG CGC TAC TCT Trp Leu Leu Asp Glu Gin Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser 130 135 140 CGG GTC ATC TGC AGT GAC AAC TAC TAT GGA GAC AAC TGC TCC CGC Tyr Arg Val lle Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg 145 150 155 160 TGC AAG AAG CGC AAT GAC CAC GGC GTG TGC CAG CCA Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gln Pro 498
37. 1362 1410 1458 1506 1554 1602 1650 1698 1746 1794 10 20 30 40 41 JP 2008 260773 2008 10 30 Asn Arg Ala Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe Val Cys 465 470 475 480 AAC TGC CCT GGC GTG GGC AGC CGC TGC GAG TTC CCC GTG GEC Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly 485 490 495 TTG CCG CCC AGC TTC CCC TGG GTG GCC GTC TCG CTG GGT GTG GGG CTG Leu Pro Pro Ser Phe Pro Trp Val Ala Yal Ser Leu Gly Val Gly Leu 500 505 510 GCA CTG CTG GTA CTG GGC ATG GTG GTG GCT GTG CGG CAG A a Val Leu Leu Val Leu Leu Gly Met Val Ala Val Ala Val Arg Gln 515 520 525 CTG CGG CTT CGA CGG CCG GAC GAC GGC AGC AGG GAA GCC ATG AAC AAC Leu Arg Leu Arg Arg Pro Asp Asp Gly Ser Arg Glu Ala Met Asn Asn 530 535 540 TTG TCG GAC TTC CAG AAG GAC AAC CTG ATT CCT GCC GCC CAG CTT Leu Ser Asp Phe Gin Lys Asp Asn Leu le Pro Ala Ala Gln Leu Lys 545 550 555 560 AAC ACA AAC CAG AAG AAG GAG GAA GTG GAC TGT GGC CTG GAC AAG Asn Thr Asn Gin Lys Lys Glu Leu Glu Val Asp Cys Gly Leu Asp Lys 565 570 575 TCC AAC TGT GGC AAA CAG AAC CAC ACA TTG GAC TAT AAT CTG GCC Ser Asn Cys Gly Lys Gin Gln Asn His Thr Leu Asp Tyr Asn Leu Ala 580 585 590 CCA GGG CCC CTG GGG CGG GGG ACC ATG CCA GGA AAG TTT CCC CAC AGT Pro Gly Pro Leu Gly Arg Gly Thr Met Pro Gly Lys Phe Pro His Ser 595 600 605 GAC AAG AGC TTA GGA GAG AAG GCG CCA CTG CGG TTA CAC AGT GAA AAG Asp Lys Ser Leu Gly Glu Lys Ala Pro
38. Thr Val Gly Glu Glu Trp Ser 125 130 135 CAG GAC CTG CAC AGC AGC GGC CGC ACG GAC CTC AAG TAC TCC TAC CGC Gin Asp Leu His Ser Ser Gly Arg Thr Asp Leu Lys Tyr Ser Tyr Arg 140 145 150 155 TTC GTG TGT GAC GAA CAC TAC TAC GGA GAG GGC TGC TCC GTT TTC TGC Phe Val Cys Asp Glu His Tyr Tyr Gly Glu Gly Cys Ser Val Phe Cys 160 165 170 CGT CGG GAC GAT GCC TTC GGC ACC GGG GAG CGT GGG Arg Pro Arg Asp Asp Ala Phe Gly His Phe Thr Cys Gly Glu Arg Gly 175 180 185 GAG AAA GTG TGC AAC CCT GGC TGG AAA GGG CCC TAC TGC ACA GAG CCG Glu Lys Val Cys Asn Pro Gly Trp Lys Gly Pro Tyr Cys Thr Glu Pro 190 195 200 ATC TGC CTG CCT GGA TGT GAT GAG CAG CAT GGA TTT TGT GAC AAA CCA Cys Leu Pro Gly Cys Asp Glu Gin His Gly Phe Cys Asp Lys Pro 514 562 610 658 106 754 802 850 898 10 20 30 40 46 JP 2008 260773 2008 10 30 205 210 215 GGG GAA TGC AAG TGC AGA GTG GGC TGG CAG GGC CGG TAC TGT GAC GAG Gly Glu Cys Lys Cys Arg Val Gly Trp Gln Gly Arg Tyr Cys Asp Glu 220 225 230 235 CGC TAT GGC CTC CAT GGC TGC CAG CAG CCC TGG Cys Arg Tyr Pro Gly Cys Leu His Gly Thr Cys Gln Pro Trp 240 245 250 CAG TGC AAC TGC CAG GAA GGC TGG GGG GGC CTT TTC TGC AAC CAG GAC Gln Cys Asn Cys Gln Glu Gly Trp Gly Gly Leu Phe Cys Asn Gln Asp 255 260 265 CTG AAC TAC TGC ACA CAC CAT AAG CCC TGC AAG AAT GGA GCC ACC TGC Leu Asn Tyr Cys Thr His His Lys Pro Cys Lys Asn Gly Ala Thr Cys 270 215 280
39. 250 255 Gin Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Ala 260 265 270 Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys Arg Pro 275 280 285 Gly Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser 290 295 300 Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp Gly Tyr 305 310 315 320 His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His Ser 32b 330 335 10 20 30 40 33 JP 2008 260773 2008 10 30 Thr Leu Ser Cys Ala Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg 340 345 350 Glu Arg Asn Gln Gly Ala Asn Tyr Ala Cys Glu Cys Pro Pro Asn Phe 300 360 365 Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro 370 315 380 Cys Ala Asn Gly Gly 1 Leu Asn Arg Gly Pro Ser Arg Met Cys 385 390 395 400 Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His Val Ser 405 410 415 Asp Cys Ala Arg Asn Pro Cys Ala His Gly Gly Thr Cys His Asp Leu 420 425 430 Glu Asn Gly Leu Met Cys Thr Cys Pro Ala Gly Phe Ser Gly Arg Arg 435 440 445 Cys Glu Val Arg Thr Ser lie Asp Ala Cys Ala Ser Ser Pro Cys Phe 450 455 460 Asn Arg Ala Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe Val Cys 465 470 475 480 Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly 485 490 495 Leu Pro Pro Ser 500 3 659 EMIR 10 20 30 40 34 JP 2008 260773 2008 10 30
40. 70 1218 1266 1314 10 20 30 40 40 JP 2008 260773 2008 10 30 CAC TGC CCT CCG GGC TAC GGC CTG CAT TGT GAA His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His Ser 325 330 335 ACC TTG AGC TGC GCC GAC TCC CCC TGC TTC AAT GGG GGC TCC TGC CGC Thr Leu Ser Cys Ala Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys 340 345 350 CGC AAC CAG GGG GCC AAC TAT GCT GAA CCC CCC AAC TTC Glu Arg Asn Gin Gly Ala Asn Tyr Ala Cys Glu Cys Pro Pro Asn Phe 355 360 365 ACC GGC TCC AAC TGC GAG AAG AAA GTG GAC AGG TGC ACC AGC AAC Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro 370 375 380 TGT GCC AAC GGG GGA CAG TGC AAC CGA CCA AGC CGC ATG TGC Cys Ala Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Met Cys 385 390 395 400 CGC TGC CGT CCT GGA TTC ACG GGC ACC TAC TGT GAA CTC CAC GTC AGC Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His Val Ser 405 410 415 GAC TGT GCC CGT AAC CCT TGC GCC CAC GGT GGC ACT TGC CAT GAC Asp Cys Ala Arg Asn Pro Cys Ala His Gly Gly Thr Cys His Asp Leu 420 425 430 GAG AAT GGG CTC ATG TGC ACC TGC CCT GCC GGC TTC TCT GCC CGA CGC Glu Asn Gly Leu Met Cys Thr Cys Pro Ala Gly Phe Ser Gly Arg Arg 435 440 445 TGT GAG CGG TCC GAT GCC TCT GCC TCG AGT CCC TGC TTC Cys Glu Val Arg Thr Ser Asp Ala Cys Ala Ser Ser Pro Cys Phe 450 455 460 AAC AGG GCC ACC TGC TAC ACC GAC CTC TCC ACA GAC ACC TTT GTG TGC
41. ACC AAC ACG GGC CAG GGG AGC TAC ACT TGC TCT TGC CGG CCT GGG TAC Thr Asn Thr Gly Gin Gly Ser Tyr Thr Cys Ser Cys Arg Pro Gly Tyr 285 290 295 ACA GGT GCC ACC TGC GAG CTG GGG ATT GAC GAG GAC AGC CCT Thr Gly Ala Thr Cys Glu Leu Gly Asp Glu Cys Asp Pro Ser Pro 300 305 310 315 AAG AAC GGA GGG AGC TGC ACG GAT CTC GAG AAC AGC TAC TCC TGT Cys Lys Asn Gly Gly Ser Cys Thr Asp Leu Glu Asn Ser Tyr Ser Cys 320 325 380 ACC TGC CCA CCC GGC TTC TAC GGC AAA ATC TGT GAA TTG AGT GCC ATG Thr Cys Pro Pro Gly Phe Tyr Gly Lys Cys Glu Leu Ser Ala Met 335 340 345 ACC TGT GCG GAC GGC CCT TGC AAC GGG GGT CGG TGC TCA GAC AGC Thr Cys Ala Asp Gly Pro Cys Phe Asn Gly Gly Arg Cys Ser Asp Ser 350 855 360 846 994 1042 1090 1188 1186 1234 1282 1330 10 20 30 40 47 JP 2008 260773 2008 10 30 COC GAT GGA GGG TAC AGC TGC CGC TGC CCC GTC GGC TAC TCC GGC TTC Pro Asp Gly Gly Tyr Ser Cys Arg Cys Pro Val Gly Tyr Ser Gly Phe 365 370 375 AAC TGT GAG AAG AAA GAC TAC TGC AGC TCT TCA CCC TGT TCT AAT Asn Cys Glu Lys Lys Ile Asp Tyr Cys Ser Ser Ser Pro Cys Ser Asn 380 385 390 395 GGT GCC AAG TGT GTG GAC CTC GGT GAT GCC TAC CTG TGC CGC TGC CAG Gly Ala Lys Cys Val Asp Leu Gly Asp Ala Tyr Leu Cys Arg Cys Gln 400 405 410 GCC GGC TTC TCG GGG AGG CAC TGT GAC GAC AAC GTG GAC GAC TGC GCC Ala Gly Phe Ser Gly Arg His Cys Asp Asp Asn Val Asp Asp Cys Ala 415 420 425 TCC TCC CCG TGC GCC AAC GGG GGC ACC TGC CGG GAT GGC G
42. AGCCCATCT CCACAACCTC GAGCCTGGGC TCTGGTCCAC 3171 TACTGCCCCA GACCACCCTC AAAGCTGGTC TTCAGAAATC AATAATATGA GTTTTTATTT 3231 TGTTTTTTTT TTITTTTTTG TGGAGTCTAG TATTTCAATA ATTTAAGAAT 3291 CAGAAGCACT GACCTTTCTA CATTTTATAA CATTATTTTG TATATAAT 3339 10 20 30 40 43 5 27 EMI DNA GAT GAT GAT GAT GAT AAA TGA Asp Tyr Lys Asp Asp Asp Asp Lys 1 5 8 6 20 SS EMR DNA TGGCARTGYA AYTGYCARGA 7 20 AAO HOR DNA CRCARTTRAA JP 2008 260773 2008 10 30 21 20 20 10 20 30 40 44 JP 2008 260773 2008 10 30 8 2653 UB HOR cDNA to mRNA CTTGGGAA GAGGCGGAGA CCGGCTTTTA AAGAAAGAAG TCCTGGGTCC TGCGGTCTGG 58 GGCGAGGCAA GGGCGCTTTT CTGCCCACGC TCOCCGTGGC CCATCGATCC CCCGCGCGTC 118 CGCCGCTGTT CTAAGGAGAG AAGTGGGGOC CCCCCAGGCT CGCGCGTGGA GCGAAGCAGC 178 ATG GGC AGT
43. Asp Lys 565 570 575 Ser Asn Cys Gly Lys Gin Gin Asn His Thr Leu Asp Tyr Asn Leu Ala 580 585 590 Pro Gly Pro Leu Gly Arg Gly Thr Met Pro Gly Lys Phe Pro His Ser 595 600 605 Asp Lys Ser Leu Gly Glu Lys Ala Pro Leu Arg Leu His Ser Glu Lys 610 615 620 Pro Glu Cys Arg Ile Ser Ala le Cys Ser Pro Arg Asp Ser Met Tyr 625 630 635 640 Gln Ser Val Cys Leu Ser Glu Arg Asn Glu Cys Val Ala 10 20 30 40 37 JP 2008 260773 A 2008 10 30 645 650 655 Thr Glu Val 659 4 3339 BAK cDNA to mRNA GCCGCC TTGGTGCAGC GTACACCGGC TT6CAGCCCC AGGATTAGAC AGAAGACGCG TCCTCGGCGC GGTC6CCGCC CAGCCGTAGT CACCTGGATT ACCTACAGCG GCAGCTGCAG CGGAGCCAGC GAGAAGGCCA AAGGGGAGCA GCGTCCCGAG AGGAGCGCCT CTTTTCAGGG ACCCCGCCGG CTGGCGGACG CGC6GGAAAG CGGCGTCOCG AACAGAGCCA GATTGAGGGC CCGCGGGTGG AGAGAGCGAC GCCCGAGGGG GCG GCA GCG TCC GCC TCT GGC Met Ala Ala Ala Ser Arg Ser Ala Ser Gly 26 25 20 TGG GCG CTA CTG GCA TGG CAG CAG CGC GCG GCC GGC Trp Ala Leu Leu Leu Leu Val Ala Leu Trp Gln Gin Arg Ala Ala Gly 15 10 5 TCC GGC GTC TTC CAG CTG CAG CTG CAG GAG TTC ATC AAC GAG CGC GGC Ser Gly Val Phe Gin Leu Gln Leu Gin Glu Phe Asn Glu Arg Gly 1 5 10 15 GTA CTG GCC AGT GGG CGG CCT TGC GAG CCC GGC TGC CGG ACT TTC TTC 16 76 136 196
44. CGG TGC GCG CTG GCC CTG GCG GTG CTC TCG GCC TTG CTG Met Gly Ser Arg Cys Ala Leu Ala Leu Ala Val Leu Ser Ala Leu Leu 20 15 10 TGT CAG GTC TGG AGC TCT GGG GTG TTC GAA CTG AAG CTG CAG GAG TTC Cys Gln Val Trp Ser Ser Gly Val Phe Glu Leu Lys Leu Gln Glu Phe 5 5 10 GTC AAC AAG AAG GGG GGG AAC COC AAC TGC TGC CGC GGG GGC Val Asn Lys Lys Gly Leu Leu Gly Asn Arg Asn Cys Cys Arg Gly Gly 15 20 25 GCG GGG CCA CCG CCG TGC GCC TGC CGG ACC TTC TTC CGC GTG TGC CTC Ala Gly Pro Pro Pro Cys Ala Cys Arg Thr Phe Phe Arg Val Cys Leu 30 35 40 AAG CAC TAC CAG GCC AGC GTG TCC CCC GAG CCG CCC TGC TAC GGC Lys His Tyr Gln Ala Ser Val Ser Pro Glu Pro Pro Cys Thr Tyr Gly 45 50 55 AGC GCC GTC ACC CCC GTG CTG GGC GTC GAC TCC TTC AGT CTG CCC GAC 226 214 322 370 418 A66 20 30 40 45 JP 2008 260773 2008 10 30 Ser Ala Val Thr Pro Val Leu 1 Val Asp Ser Phe Ser Leu Pro Asp 60 65 10 75 GGC GGG GCC GAC TCC GCG TTC AGC AAC ATC CGC TTC CCC TTC Gly Gly Gly Ala Asp Ser Ala Phe Ser Asn Pro Arg Phe Pro Phe 80 85 90 GGC ACC CCG GGC ACC TTC TCT ATT GAA GCT CTC CAC Gly Phe Thr Trp Pro Gly Thr Phe Ser Leu Ile Glu Ala Leu His 95 100 105 ACA GAT TCT CCT GAT GAC CTC GCA ACA GAA AAC CCA GAA AGA CTC ATC Thr Asp Ser Pro Asp Asp Leu Ala Thr Glu Asn Pro Glu Arg Leu Ile 110 115 120 AGC CGC CTG GCC ACC CAG AGG CAC CTG ACG GTG GGC GAG GAG TGG TCC Ser Arg Leu Ala Thr Gin Arg His Leu
45. GCCTGTC 2527 GCGGCCCGGC CGCCTGCGGC ACTGCCTTCC GTGACGTCGC CGTTGCACTA TGGACAGTTG 2587 CTCTTAAGAG AATATATATT TAAATGGGTG AACTGAATTA CGCATAAGAA GCATGCACTG 2647 CCTGAGTGTA TATTTT 2663 9 2 0 DNA TGACGGTGGG CGAGGAGTGG 20 10 20 10 20 30 40 50 JP 2008 260773 2008 10 30 BAR DNA GCAGCTGTAC CCTCCATCGG 11 716 ASR cDNA to mRNA TGACGGTGGG CGAGGAGTGG TCCCAGGACC TGCACAGCAG CGGCCGCACG GACCTCAAGT ACTCCTACCG CTTCGTGTGT GACGAACACT ACTACGGAGA GGGCTGCTCC GTTTTCTGCC CGATGCCTTC GGCCACTTCA CCTGTGGGGA GCGTGGGGAG AAAGTGTGCA ACCCTGGCTG GAAAGGGCCC TACTGCACAG AGCCGATCTG CCTGCCTGGA TGTGATGAGC AGCATGGATT TTGTGACAAA CCAGGGGAAT GCAAGTGCAG AGTGGGCTGG CAGGGCCGGT ACTGTGACGA GTGTATCOGC TATCCAGGCT GTCTCCATGG CACCTGCCAG CAGCCCTGGC AGTGCAACTG CCAGGAAGGC TGGGGGGGCC TTTTCTGCAA CCAGGACCTG AACTACTGCA CACACCATAA GCCCTGCAAG AATGGAGCCA CCTGCACCAA CACGGGCCAG GGGAGCTACA CTTGCTCTTG CCGGCCTGGG TACACAGGTG CCACCTGOGA GCTGGGGATT GACGAGTGTG ACCCCAGCCC TTGTAAGAAC GGAGGGAGC
46. HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH HHHHHHHHHHHHHHHHHHH HHHHHHH JP 2008 260773 2008 10 30 2 10 l uH 20 30 40 ID DU l ID 50
47. JP 2008 260773 2008 10 30 19 JP a2 4s BB Fe PT BRA 11 2008 260773 P2008 260773A 43 20 10 30 2008 10 30 51 Int Cl Fl A61K 38 00 2006 01 A61K 37 02 ZNA 4CO84 A61P 35 0 2006 01 AGIP 35 00 4HO45 AG1P 43 0 26 01 A61P 43 0 105 CO7K 14 705 2006 01 COT7K 14 705 5 OL 58 21 2008 123043 P2008 123043 71 000000033 22 20 5 9 2008 5 9 62 10 549046 1 2 6 10 5 13 1998 5 13 74 110000109 31 9 124064 32 9 5 14 1997 5 13 72 1 2 JH F 4C084 AA02 BAO2 BAO8 BA22 CA26 DA27 NAI4 28262 4H045 AA10 BAIO CA40 DA50 EA24 FA74 33 JP 54 57 0 000 IlHHH
48. Leu Arg Leu His Ser Glu Lys 1842 1890 1938 1986 2034 2082 2130 2178 2226 10 20 30 40 42 JP 2008 260773 2008 10 30 610 615 620 CCA GAG TGT CGG ATA TCA GCG ATA TGC TCC CCC AGG GAC TCC ATG 2274 Pro Glu Cys Arg Ile Ser Ala Ile Cys Ser Pro Arg Asp Ser Met Tyr 625 630 635 640 CAG TCT GTG TGT TTG ATA TCA GAG GAG AGG AAT GAA TGT GTC ATT GCC 2322 Ser Val Cys Leu Ser Glu Glu Arg Asn Glu Cys Val Ala 645 650 655 ACG GAG GTA 2331 Thr Glu Val 659 TAAGGCAGGA GCCTACCTGG ACATCCCTGO TCAGCCCCGC GGCTGGACCT TCCTTCTGCA 2391 TTGTTTACAT TGCATCCTGG ATGGGACGTT AACGTGCTGC TCTCAGGAGG 2451 AGGAGGGAAT GGCAGGAACC GGACAGACTG TGAACTTGCC AAGAGATGCA ATACCCTTCC 2511 ACACCTTTGG GTGTCTGTCT GGCATCAGAT TGGCAGCTGC ACCAACCAGA GGAACAGAAG 2571 AGAAGAGAGA TGCCACTGGG CACTGCCCTG CCAGTAGTGG CCTTCAGGGG GCTCCTTCCG 2631 GGGCTCCGGC CTGTTTTCCA GAGAGAGTGG CAGTAGCCCC ATGGGGCCCG GAGCTGCTGT 2691 GbCCTCCACT GGCATCCGTG TTTCCAAAAG TGCCTTTGGC CCAGGCTCCA C6GCGACAGT 2751 TGGGCCCAAA TCAGAAAGGA GAGAGGGGGC CAATGAGGGC AGGGCCTCCT GTGGGCTGGA 2811 AAACCACTGG GTGCGTCTICT TGCTGGGGTT TGCCCTGGAG GTGAGCTGAG TGCTCGAGGG 2871 AGGGGAGTGC TTTCTGCCCC ATGCCTCCAA CTACTGTATG CAGGCCTGGC TCTCTGGTCT 2931 AGGCCCTTTG GGCAAGAATG TCCGTCTACC CGGCTTCCAC CACCCTCTGG CCCTGGGCTT 2991 CTGTAAGCAG ACAGGCAGAG GGCCTGCCCC TCCCACCAGC CAAGGGTGCC AGGCCTAACT 3051 GGGGCACTCA GGGCAGTGTG TTGGAAATTC CACTGAGGGG GAAATCAGGT GCTGCGGCCG 3111 CCTGGGCCCT TTCCTCCCTC A
49. T GCACGGATCT CGAGAACAGC TACTCCTGTA CCTGCCCACC CGGCTTCTAC GGCAAAATCT GTGAATTGAG TGCCATGACC TGTGCGGACG CCCTTGCTT TAACGGGGGT CGGTGCTCAG ACAGCCCCGA TGGAGGGTAC AGCTGC 20 60 120 180 240 300 360 420 480 540 600 660 716 10 20 30 40 51 JP 2008 260773 2008 10 30 12 20 EMR DNA TTGGGCACCA ACTCCTTCGC 20 13 2 0 DNA TAGGCTGTTG GCAATATTCC 20 14 412 HOR ZEH EAR cDNA to mRNA TTGGGCACCA ACTCCTTCGC TGTCCGGGAC GACAGTAGCG GCGGGGGGCG CAACCCTCTC 60 CAACTGCCCT TCAATTTCAC CTGGCCGGGT ACCTTCTCGC TCATCATCGA AGCTTGGCAC 120 10 20 30 40 52 JP 2008 260773 2008 10 30 GCGCCAGGAG ACGACCTGCG GCCAGAGGCC TTGCCACCAG ATGCACTCAT CAGCAAGATC GCCATCCAGG GCTCCCTAGC TGTGGGTCAG AACTGGTTAT TGGATGAGCA AACCAGCACC CTCACAAGGC TGCGCTACTC TTACCGGGTC ATCTGCAGTG ACAACTACTA TGGAGACAAC TGCTCCCGCC TGTGCAAGAA GCGCAATGAC CACTTCGGCC ACTATGTGTG CCAGCCAGAT GGCAACTTGT CCTGCCTGCC CGGTTGGACT GGGGAATATT GCCAACAGCC TA 15 28
50. TG AAC GAC Ser Ser Pro Cys Ala Asn Gly Gly Thr Cys Arg Asp Gly Val Asn Asp 430 435 440 TTC TCC TGC CCG CCT GGC TAC ACG GGC AGG AAC TGC AGT GCC Phe Ser Cys Thr Cys Pro Pro Gly Tyr Thr Gly Arg Asn Cys Ser Ala 445 450 455 CCC GTC AGC AGG TGC GAG CAC GCA CCC TGC CAC AAT GGG GCC ACC TGC Pro Val Ser Arg Cys Glu His Ala Pro Cys His Asn Gly Ala Thr Cys 460 465 470 475 CAC GAG AGG GGC CAC CGC GTG TGC GAG GCC CGA GGC TAC GGG His Glu Arg Gly His Arg Tyr Val Cys Glu Cys Ala Arg Gly Tyr Gly 480 485 490 GGT CCC TGC CAG TTC CTG CTC CCC GAG CTG CCC CCG GGC CCA GCG Gly Pro Asn Cys Gln Phe Leu Leu Pro Glu Leu Pro Pro Gly Pro Ala 495 500 505 GTG GTG GAC CTC ACT GAG AAG GAG GGC CAG GGC GGG CCA TTC CCC 1378 1426 1474 1522 1570 1618 1666 1714 1162 1810 10 20 30 40 48 JP 2008 260773 2008 10 30 Val Val Asp Leu Thr Glu Lys Leu Glu Gly Gln Gly Gly Pro Phe Pro 510 515 520 TGG GTG GCC GTG TGC GCC GGG GTC ATC CTT GTC CTC ATG CTG CTG Trp Val Ala Val Cys Ala Gly Val Ile Leu Val Leu Met Leu Leu Leu 525 530 595 GGC TGT GCC GCT GTG GTG GTC TGC GTC CCG AGG CTG CAG AAG Gly Cys Ala Ala Val Val Val Cys Val Arg Leu Arg Leu Gln Lys His 540 545 550 555 CGG CCC GCC CCC TGC CGG GGG GAG ACG GAG ACC ATG AAC AAC Arg Pro Pro Ala Asp Pro Cys Arg Gly Glu Thr Glu Thr Met Asn Asn 566 565 570 CTG GCC AAC TGC CAG CGT GAG AAG GAC ATC TCA GTC AGC ATC ATC GGG Leu Ala Asn Cy
51. ro 275 280 285 Gly Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser 290 295 800 Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gin Glu Asp Gly 305 310 315 320 His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His Ser 325 330 385 Thr Leu Ser Cys Ala Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg 340 345 350 Glu Arg Asn Gin Gly Ala Asn Tyr Ala Cys Glu Cys Pro Pro Asn Phe 355 360 365 Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro 370 375 380 Cys Ala Asn Gly Gly Gin Cys Leu Asn Arg Gly Pro Ser Arg Met Cys 385 390 395 400 Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His Val Ser 405 410 415 Asp Cys Ala Arg Asn Pro Cys Ala His Gly Gly Thr Cys His Asp Leu 10 20 30 40 36 JP 2008 260773 2008 10 30 420 425 480 Glu Asn Gly Leu Met Cys Thr Cys Pro Ala Gly Phe Ser Gly Arg Arg 435 440 445 Cys Glu Val Arg Thr Ite Asp Ala Cys Ala Ser Ser Pro Cys Phe 450 455 460 Asn Arg Ala Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe Val Cys 465 470 475 480 Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly 485 490 495 Leu Pro Pro Ser Phe Pro Trp Val Ala Val Ser Leu Gly Val Gly Leu 500 505 510 Ala Val Leu Leu Vai Leu Leu Gly Met Val Ala Val Ala Val Arg Gln 515 520 525 Leu Leu Arg Pro Asp Asp Gly Ser Arg Glu Ala Met Asn Asn 530 535 540 Leu Ser Asp Phe Lys Asp Asn Leu Pro Ala Ala Leu Lys 545 550 555 560 Asn Thr Asn Gln Lys Lys Glu Leu Glu Val Asp Cys Gly Leu
52. s Gln Arg Glu Lys Asp Ile Ser Val Ser Ile Gly 575 580 585 GCC ACG CAG ATC AAG AAC ACC AAC AAG AAG GCG GAC TTC CAC GGG GAC Ala Thr Gln Lys Asn Thr Asn Lys Lys Ala Asp Phe His Gly Asp 590 595 600 CAC AGC GCC GAC AAG AAT GGC TTC AAG GCC CGC TAC CCA GCG GTG GAC His Ser Ala Asp Lys Asn Gly Phe Lys Ala Arg Tyr Pro Ala Val Asp 605 610 615 TAT AAC CTC GTG CAG GAC CTC AAG GGT GAC GAC ACC GCC GTC AGG GAC Tyr Asn Leu Val Gin Asp Leu Lys Gly Asp Asp Thr Ala Val Arg Asp 620 625 630 685 GCG AGC AAG CGT GAC ACC AAG TGC CAG CCC CAG GGC TCC TCA GGG Ala His Ser Lys Arg Asp Thr Lys Cys Pro Gln Gly Ser Ser Gly 640 645 650 GAG AAG GGG ACC COG ACC ACA CTC AGG GGT GGA GAA GCA TCT GAA Glu Glu Lys Gly Thr Pro Thr Thr Leu Arg Gly Gly Glu Ala Ser Glu 1858 1906 1954 2002 2050 2098 2146 2194 2242 10 20 30 40 49 JP 2008 260773 2008 10 30 655 660 665 AGA AAA AGG CCG GAC TCG GGC TCA ACT TCA GAC ACC AAG 2290 Arg Lys Arg Pro Asp Ser Gly Cys Ser Thr Ser Lys Asp Thr Lys Tyr 670 675 680 TCG CTG GTC ATA TCC GAG GAG AAG GAT GAG TGC GTC GCA 2338 Ser Val Tyr Val Ser Glu Glu Lys Asp Glu Cys Ile Ala 685 690 695 ACT GAG GTG 2347 Thr Glu Val 700 TAAAATGGAA GTGAGATGGC AAGACTCCCG TTTCTCTTAA AATAAGTAAA ATTCCAAGGA 2407 TATATGCCCC AACGAATGCT GCTGAAGAGG AGGGAGGCCT CGTGGACTGC TGCTGAGAAA 2467 ACCGAGCAGG TTCTCCTCCT GAGGTCCTCG ACGCCTGCCG ACA
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