KEGG ID: 04310
KEGG Diagram for Wnt signaling pathway
There are 115 IPI Records from this pathway found in Rattus norvegicus.
Location of Wnt signaling pathway proteins on Rat Genome
| IPI Record | Position |
|---|---|
| 1: Apc | 18:26732147-26790383 |
| 2: Apc2_predicted | 7:10906423-10920010 |
| 3: Axin1 | 10:15409373-15462726 |
| 4: Axin2 | 10:98294466-98321846 |
| 5: Btrc | 1:250585384-250693952 |
| 6: Camk2a | 18:56879142-56948262 |
| 7: Camk2b | 14:86634690-86721261 |
| 8: Camk2d | 2:224021416-224106433 |
| 9: Camk2g | :- |
| 10: Ccnd1 | 1:205360031-205366632 |
| 11: Ccnd2 | 4:163523817-163546501 |
| 12: Ccnd3 | :- |
| 13: Chd8 | 15:27643081-27681116 |
| 14: Chp | 3:106066389-106101638 |
| 15: Crebbp | 10:11598680-11724122 |
| 16: Csnk1a1 | 18:57541673-57564601 |
| 17: Csnk1e | 7:117401336-117420764 |
| 18: Csnk2a1 | 3:142588572-142609301 |
| 19: Csnk2a2_predicted | 19:10015349-10049896 |
| 20: Csnk2b | 20:3764565-3768982 |
| 21: Ctbp1 | 14:83022822-83050339 |
| 22: Ctbp2 | 1:192463397-192502700 |
| 23: Ctnnb1 | 8:125978161-125987670 |
| 24: Cxxc4 | 2:231705560-231722975 |
| 25: Dkk1_predicted | 1:234393440-234396308 |
| 26: Dkk4_predicted | 2:229542605-229633223 |
| 27: Dvl1 | 5:172705803-172717699 |
| 28: Dvl3_predicted | 11:82597767-82622175 |
| 29: Fbxw11_predicted | 10:17538864-17597963 |
| 30: Fosl1 | 1:208090612-208099118 |
| 31: Fzd1 | 4:25994423-25998574 |
| 32: Fzd2 | 10:91709222-91711132 |
| 33: Fzd3 | :- |
| 34: Fzd4 | 1:145953741-145957666 |
| 35: Fzd5 | :- |
| 36: Fzd6 | 7:74563294-74592245 |
| 37: Fzd7_predicted | :- |
| 38: Fzd9 | 12:22581510-22583824 |
| 39: Gsk3b | 11:64284731-64428698 |
| 40: IPI00202282 | 7:137557971-137561928 |
| 41: Jun | 5:115359397-115360401 |
| 42: Lef1 | 2:228550263-228689323 |
| 43: Map3k7_predicted | 5:48252637-48308832 |
| 44: Mapk10 | 14:7865731-8010694 |
| 45: Mapk8 | 16:8925133-8954535 |
| 46: Mapk9 | 10:35344672-35384319 |
| 47: MGC112790 | 17:65966634-65971954 |
| 48: Mmp7 | 8:4526018-4533724 |
| 49: Myc | 7:98953142-98957835 |
| 50: Nfat5_predicted | 19:37088893-37241536 |
| 51: Nfatc2_predicted | 3:159654343-159773666 |
| 52: Nfatc3_predicted | 19:35907874-35979801 |
| 53: Nfatc4 | 15:33969620-33978926 |
| 54: Peg12_predicted | :- |
| 55: Plcb1 | 3:122799444-123522328 |
| 56: Plcb2 | 3:105197784-105223342 |
| 57: Plcb3 | 1:209628300-209643682 |
| 58: Plcb4 | 3:123861013-124077386 |
| 59: Ppard | 20:6479092-6543024 |
| 60: Ppp2ca | 10:37621256-37641006 |
| 61: Ppp2cb | 16:62330513-62351968 |
| 62: Ppp2r1a | 1:58442220-58461462 |
| 63: Ppp2r2a | 15:46545988-46603956 |
| 64: Ppp2r2b | 18:35866177-36318168 |
| 65: Ppp2r2c | 14:79436062-79515914 |
| 66: Ppp2r2d | 1:198640963-198674516 |
| 67: Ppp3ca | 2:234333405-234408670 |
| 68: Ppp3cb | 15:4003159-4022737 |
| 69: Ppp3cc | 15:50616841-50666010 |
| 70: Ppp3r1 | 14:98047333-98131590 |
| 71: Ppp3r2 | 5:66423374-66424371 |
| 72: Prickle1 | 7:131967780-131978681 |
| 73: Prkaca | 19:25837118-25864844 |
| 74: Prkacb | 2:244946188-245002604 |
| 75: Prkca | 10:97361597-97625118 |
| 76: Prkcb1 | 1:181118102-181459480 |
| 77: Prkcc | 1:64145733-64172745 |
| 78: Psen1 | 6:107737543-107776357 |
| 79: Rac1 | 12:11380314-11400531 |
| 80: Rac2 | 7:116520066-116532482 |
| 81: RGD1560225_predicted | 18:77531419-77593552 |
| 82: RGD1561602_predicted | 10:64681467-64804864 |
| 83: RGD1564947_predicted | X:26317399-26330180 |
| 84: Rhoa | :- |
| 85: Rock1 | 18:1366989-1511865 |
| 86: Rock2 | 6:40581295-40667231 |
| 87: Ruvbl1 | 4:122556839-122591766 |
| 88: Senp2 | 11:81225720-81259934 |
| 89: Sfrp1 | 16:73030329-73083312 |
| 90: Sfrp2 | 2:175479310-175486882 |
| 91: Sfrp4 | 17:53121425-53131521 |
| 92: Siah1a | 19:21717141-21740753 |
| 93: Smad2 | 18:73180290-73241713 |
| 94: Smad3 | 8:67803909-67952056 |
| 95: Smad4 | 18:70432832-70461485 |
| 96: Sox17_predicted | 5:15244441-15246899 |
| 97: Tcf3_predicted | 4:106128505-106149235 |
| 98: Tcf7_predicted | 10:37687192-37716600 |
| 99: Tp53 | 10:56399668-56411149 |
| 100: Wif1 | 7:60330517-60400697 |
| 101: Wnt10a_predicted | 9:74124609-74137508 |
| 102: Wnt10b_predicted | 7:137541213-137547019 |
| 103: Wnt11 | 1:156121882-156141328 |
| 104: Wnt16 | 4:48609795-48620311 |
| 105: Wnt2 | 4:43648918-43689589 |
| 106: Wnt2b | 2:200218639-200233002 |
| 107: Wnt3_predicted | 10:92916324-92964379 |
| 108: Wnt4 | 5:156064350-156083190 |
| 109: Wnt5a | 16:3782025-3799625 |
| 110: Wnt5b | 4:155748108-155765586 |
| 111: Wnt6_predicted | 9:74104431-74117634 |
| 112: Wnt7a | 4:125541685-125586461 |
| 113: Wnt8a_predicted | 18:27002824-27012178 |
| 114: Wnt9a_predicted | 10:45598195-45639344 |
| 115: Wnt9b_predicted | 10:92883549-92901588 |
There are 115 IPI Records from this pathway found in Mus musculus.
Location of Wnt signaling pathway proteins on Mouse Genome
| IPI Record | Position |
|---|---|
| 1: Apc | 18:34345794-34443382 |
| 2: Apc2 | 10:79704967-79719154 |
| 3: Axin1 | 17:25866334-25923411 |
| 4: Axin2 | 11:108736456-108766873 |
| 5: Btrc | 19:45417062-45583324 |
| 6: Cacybp | 1:162039046-162049422 |
| 7: Camk2a | 18:61050987-61113521 |
| 8: Camk2b | 11:5869675-5965751 |
| 9: Camk2d | 3:126588995-126837076 |
| 10: Camk2g | 14:19523427-19582640 |
| 11: Ccnd1 | 7:144739321-144749220 |
| 12: Ccnd2 | 6:127091327-127116667 |
| 13: Ccnd3 | 17:46968322-47062874 |
| 14: Cer1 | 4:82352982-82356382 |
| 15: Chd8 | 14:51146552-51159523 |
| 16: Crebbp | 16:3999276-4128632 |
| 17: Csnk1a1 | 18:61680702-61713672 |
| 18: Csnk1e | 15:79245107-79266120 |
| 19: Csnk2a1 | 2:151918326-151973281 |
| 20: Csnk2a2 | 8:98337108-98377956 |
| 21: Csnk2b | 17:34724251-34729503 |
| 22: Ctbp1 | 5:33564581-33591839 |
| 23: Ctbp2 | 7:132825906-132961691 |
| 24: Ctnnb1 | 9:120782173-120809205 |
| 25: Ctnnbip1 | 4:148362043-148410525 |
| 26: Cul1 | 6:47383910-47455725 |
| 27: Cxxc4 | 3:134173884-134199367 |
| 28: Daam1 | 12:72749655-72910944 |
| 29: Daam2 | 17:48923992-49029920 |
| 30: Dkk1 | 19:30611873-30615493 |
| 31: Dkk2 | 3:132022607-132117616 |
| 32: Dkk4 | 8:24089588-24093092 |
| 33: Dvl1 | 4:154691212-154703103 |
| 34: Dvl2 | 11:69816790-69828496 |
| 35: Dvl3 | 16:20430525-20445059 |
| 36: Fbxw11 | 11:32542748-32646816 |
| 37: Fosl1 | 19:5447698-5455938 |
| 38: Frat1 | :- |
| 39: Frat2 | 19:41900527-41901222 |
| 40: Fzd1 | 5:4761658-4763586 |
| 41: Fzd10 | :- |
| 42: Fzd2 | 11:102420623-102424144 |
| 43: Fzd3 | 14:64156448-64216534 |
| 44: Fzd4 | 7:89279586-89285277 |
| 45: Fzd5 | 1:64668689-64672026 |
| 46: Fzd6 | 15:38836426-38868268 |
| 47: Fzd7 | 1:59426725-59431505 |
| 48: Fzd8 | 18:9212918-9214975 |
| 49: Fzd9 | 5:135533878-135535656 |
| 50: Gsk3b | 16:38008240-38165318 |
| 51: Jun | 4:94542255-94544189 |
| 52: Lef1 | 3:131099626-131213476 |
| 53: Lrp5 | 19:3584836-3686546 |
| 54: Lrp6 | 6:134416479-134507739 |
| 55: Map3k7 | 4:32292729-32349408 |
| 56: Mapk10 | 5:103148770-103149081 |
| 57: Mapk8 | 14:32209888-32276220 |
| 58: Mapk9 | 11:49690177-49729834 |
| 59: Mmp7 | 9:7692146-7699125 |
| 60: Myc | 15:61815052-61820027 |
| 61: Nfat5 | 8:110182688-110268637 |
| 62: Nfatc1 | 18:80797750-80875130 |
| 63: Nfatc2 | 2:168167615-168292860 |
| 64: Nfatc3 | 8:108948972-109017574 |
| 65: Nfatc4 | 14:54779079-54788014 |
| 66: Nkd1 | 8:91411459-91483156 |
| 67: Nkd2 | 13:74286135-74313614 |
| 68: Nlk | 11:78383361-78513568 |
| 69: Plcb1 | 2:134477974-135163721 |
| 70: Plcb3 | 19:7020758-7036804 |
| 71: Plcb4 | 2:135496989-135704509 |
| 72: Porcn | X:7350808-7363450 |
| 73: Ppard | 17:27960392-28029058 |
| 74: Ppp2ca | 11:51942247-51966172 |
| 75: Ppp2cb | 8:35065560-35085738 |
| 76: Ppp2r1a | 17:20650151-20670602 |
| 77: Ppp2r1b | 9:50609165-50646459 |
| 78: Ppp2r2b | 18:42763405-43184571 |
| 79: Ppp2r2c | 5:37156819-37243329 |
| 80: Ppp2r2d | 7:138684702-138721397 |
| 81: Ppp3ca | 3:136608220-136874773 |
| 82: Ppp3cb | 14:19288592-19335096 |
| 83: Ppp3cc | 14:68953164-69002587 |
| 84: Ppp3r1 | :- |
| 85: Ppp3r2 | 4:49699847-49703083 |
| 86: Prickle1 | 15:93327294-93424071 |
| 87: Prickle2 | 6:92341392-92532870 |
| 88: Prkaca | 8:86863093-86889980 |
| 89: Prkacb | 3:146666960-146750346 |
| 90: Prkca | 11:107754338-108159844 |
| 91: Prkcb1 | 7:122080445-122419803 |
| 92: Prkcc | :- |
| 93: Prkx | X:74014742-74048679 |
| 94: Psen1 | 12:84577950-84624947 |
| 95: Rac1 | 5:143761100-143783654 |
| 96: Rac2 | 15:78386424-78400038 |
| 97: Rac3 | 11:120537558-120540059 |
| 98: Rbx1 | 15:81293628-81301187 |
| 99: Rhoa | 9:108164298-108196026 |
| 100: Rock1 | 18:10067465-10181315 |
| 101: Rock2 | 12:16920670-17003586 |
| 102: Ruvbl1 | 6:88431098-88463206 |
| 103: Senp2 | 16:21924664-21963134 |
| 104: Sfrp1 | 8:24877063-24915179 |
| 105: Sfrp2 | 3:83852248-83860242 |
| 106: Sfrp4 | 13:19630648-19640286 |
| 107: Sfrp5 | 19:42251282-42255442 |
| 108: Siah1a | 8:89614112-89636039 |
| 109: Siah1b | X:159414808-159420245 |
| 110: Skp1a | 11:52080260-52089443 |
| 111: Smad2 | 18:76367274-76431096 |
| 112: Smad3 | 9:63444773-63556000 |
| 113: Smad4 | :- |
| 114: Sox17 | 1:4481009-4486494 |
| 115: Tbl1x | X:73894169-73911524 |
| 116: Tbl1xr1 | 3:22267857-22402606 |
| 117: Tcf3 | 6:72555889-72718465 |
| 118: Tcf7 | 11:52096027-52126602 |
| 119: Tcf7l2 | 19:55795070-55986503 |
| 120: Trp53 | 11:69396600-69407992 |
| 121: Vangl1 | :- |
| 122: Vangl2 | 1:173839265-173865119 |
| 123: Wif1 | 10:120437064-120503703 |
| 124: Wnt1 | 15:98617891-98621868 |
| 125: Wnt10a | 1:74724723-74737386 |
| 126: Wnt10b | 15:98598750-98606184 |
| 127: Wnt11 | 7:98711321-98730387 |
| 128: Wnt16 | 6:22238231-22248523 |
| 129: Wnt2 | 6:17938940-17980356 |
| 130: Wnt2b | 3:105072861-105089765 |
| 131: Wnt3 | 11:103590314-103634047 |
| 132: Wnt3a | 11:59064228-59106947 |
| 133: Wnt4 | 4:136549711-136568855 |
| 134: Wnt5a | 14:27332339-27352300 |
| 135: Wnt5b | 6:119398153-119509937 |
| 136: Wnt6 | 1:74705165-74718155 |
| 137: Wnt7a | 6:91329487-91376873 |
| 138: Wnt7b | 15:85363211-85409587 |
| 139: Wnt8a | 18:34667114-34673074 |
| 140: Wnt8b | 19:44546783-44566123 |
| 141: Wnt9a | 11:59123123-59147570 |
| 142: Wnt9b | 11:103543453-103565911 |
There are 115 IPI Records from this pathway found in Homo sapiens.
Location of Wnt signaling pathway proteins on Human Genome
| IPI Record | Position |
|---|---|
| 1: APC | 5:112101483-112209834 |
| 2: APC2 | 19:1401148-1424243 |
| 3: AXIN1 | 16:277441-342465 |
| 4: AXIN2 | 17:60955143-60988227 |
| 5: BTRC | 10:103103810-103307068 |
| 6: CACYBP | 1:173235194-173247786 |
| 7: CAMK2A | 5:149582736-149649485 |
| 8: CAMK2B | 7:44225422-44331749 |
| 9: CAMK2D | 4:114593022-114902177 |
| 10: CAMK2G | 10:75242265-75304349 |
| 11: CCND1 | 11:69165054-69178422 |
| 12: CCND2 | 12:4253199-4284777 |
| 13: CCND3 | 6:42010649-42124404 |
| 14: CER1 | 9:14709722-14712715 |
| 15: CHD8 | 14:20923485-20975242 |
| 16: CHP | 15:39310729-39361369 |
| 17: CREBBP | 16:3716572-3870723 |
| 18: CSNK1A1 | 5:148855038-148911200 |
| 19: CSNK1A1L | 13:36575396-36577801 |
| 20: CSNK1E | 22:37017870-37124473 |
| 21: CSNK2A1 | 20:411340-472482 |
| 22: CSNK2A2 | 16:56749320-56789283 |
| 23: CTBP1 | 4:1195228-1232925 |
| 24: CTBP2 | 10:126666894-126839072 |
| 25: CTNNB1 | 3:41216004-41256938 |
| 26: CTNNBIP1 | 1:9830921-9892981 |
| 27: CUL1 | 7:148058024-148129056 |
| 28: CXXC4 | 4:105609015-105635500 |
| 29: DAAM1 | 14:58725151-58906224 |
| 30: DAAM2 | 6:39868137-39980622 |
| 31: DKK1 | 10:53744064-53747595 |
| 32: DKK2 | 4:108062418-108176903 |
| 33: DKK4 | 8:42350744-42353832 |
| 34: DVL1 | 1:1260521-1274623 |
| 35: DVL2 | 17:7069384-7078592 |
| 36: DVL3 | 3:185355978-185374092 |
| 37: EP300 | 22:39817736-39905472 |
| 38: FBXW11 | 5:171221161-171366482 |
| 39: FOSL1 | 11:65416268-65424573 |
| 40: FRAT1 | 10:99069012-99071662 |
| 41: FRAT2 | 10:99082244-99084456 |
| 42: FZD1 | 7:90731719-90736059 |
| 43: FZD10 | 12:129212957-129216237 |
| 44: FZD2 | 17:39990353-39992382 |
| 45: FZD3 | 8:28407692-28487707 |
| 46: FZD4 | 11:86334370-86344081 |
| 47: FZD5 | 2:208338962-208342363 |
| 48: FZD6 | 8:104379843-104414214 |
| 49: FZD7 | 2:202607555-202611405 |
| 50: FZD8 | 10:35967183-35970368 |
| 51: FZD9 | 7:72486045-72488386 |
| 52: GSK3B | 3:121028238-121295954 |
| 53: JUN | 1:59019048-59022587 |
| 54: LEF1 | 4:109188150-109309027 |
| 55: LOC652788 | :- |
| 56: LRP5 | 11:67836674-67973301 |
| 57: LRP6 | 12:12164958-12311013 |
| 58: MAP3K7 | 6:91280013-91353485 |
| 59: MAPK10 | 4:87156656-87511051 |
| 60: MAPK8 | 10:49184739-49317409 |
| 61: MAPK9 | 5:179595388-179640218 |
| 62: MMP7 | 11:101896450-101906688 |
| 63: MYC | 8:128817498-128822853 |
| 64: NFAT5 | 16:68156498-68296054 |
| 65: NFATC1 | 18:75256760-75390310 |
| 66: NFATC2 | 20:49441083-49592665 |
| 67: NFATC3 | 16:66676845-66818301 |
| 68: NFATC4 | 14:23907094-23918645 |
| 69: NKD1 | 16:49139742-49226142 |
| 70: NKD2 | 5:1061944-1091925 |
| 71: NLK | 17:23393309-23547529 |
| 72: PLCB1 | 20:8060908-8813547 |
| 73: PLCB2 | 15:38367402-38387330 |
| 74: PLCB3 | 11:63775623-63791970 |
| 75: PLCB4 | 20:9024932-9409889 |
| 76: PORCN | X:48252307-48264359 |
| 77: PPARD | 6:35418320-35503933 |
| 78: PPP2CA | 5:133560047-133589849 |
| 79: PPP2CB | 8:30762683-30789894 |
| 80: PPP2R1A | 19:57385046-57421482 |
| 81: PPP2R1B | 11:111102848-111142345 |
| 82: PPP2R2A | 8:25098204-26284562 |
| 83: PPP2R2B | 5:145949265-146415783 |
| 84: PPP2R2C | 4:6373209-6525074 |
| 85: PPP3CA | 4:102163610-102487376 |
| 86: PPP3CB | 10:74866192-74925765 |
| 87: PPP3CC | 8:22354541-22454580 |
| 88: PPP3R1 | :- |
| 89: PPP3R2 | 9:103393718-103397104 |
| 90: PRICKLE1 | 12:41139341-41269745 |
| 91: PRICKLE2 | 3:64054594-64186171 |
| 92: PRKACA | 19:14063509-14089559 |
| 93: PRKACB | 1:84316329-84476769 |
| 94: PRKACG | 9:70817241-70818849 |
| 95: PRKCA | 17:61729388-62237324 |
| 96: PRKCB1 | 16:23754823-24139358 |
| 97: PRKCG | 19:59077279-59102713 |
| 98: PRKX | X:3532415-3641661 |
| 99: PRKY | Y:7202013-7309589 |
| 100: PSEN1 | 14:72672915-72756862 |
| 101: RAC1 | 7:6380651-6410120 |
| 102: RAC2 | 22:35951238-35970241 |
| 103: RAC3 | 17:77582821-77585366 |
| 104: RBX1 | 22:39677331-39698628 |
| 105: RHOA | 3:49371585-49424530 |
| 106: ROCK1 | 18:16787533-16944869 |
| 107: ROCK2 | 2:11239229-11402162 |
| 108: RUVBL1 | 3:129282493-129325350 |
| 109: SENP2 | 3:186786725-186831577 |
| 110: SFRP1 | 8:41238640-41286149 |
| 111: SFRP2 | 4:154921194-154929678 |
| 112: SFRP4 | 7:37912247-37922903 |
| 113: SFRP5 | 10:99516369-99521727 |
| 114: SIAH1 | 16:46947778-47039814 |
| 115: SKP1A | 5:133520468-133540583 |
| 116: SMAD2 | 18:43618435-43711221 |
| 117: SMAD3 | 15:65145249-65274586 |
| 118: SMAD4 | 18:46810611-46860142 |
| 119: SOX17 | 8:55533048-55535484 |
| 120: TBL1X | X:9391369-9647777 |
| 121: TBL1XR1 | 3:178221867-178397734 |
| 122: TBL1Y | Y:6838727-7019724 |
| 123: TCF7 | 5:133478301-133511826 |
| 124: TCF7L1 | 2:85214245-85391012 |
| 125: TCF7L2 | 10:114700201-114917427 |
| 126: TP53 | 17:7512464-7531642 |
| 127: VANGL1 | 1:115986120-116037841 |
| 128: VANGL2 | 1:158636988-158665088 |
| 129: WIF1 | 12:63730674-63801383 |
| 130: WNT1 | 12:47658503-47662746 |
| 131: WNT10A | 2:219453488-219466889 |
| 132: WNT10B | 12:47645391-47651548 |
| 133: WNT11 | 11:75575018-75595222 |
| 134: WNT16 | 7:120752657-120768393 |
| 135: WNT2 | 7:116704518-116750579 |
| 136: WNT2B | 1:112810686-112866811 |
| 137: WNT3 | 17:42196863-42251081 |
| 138: WNT3A | 1:226261375-226315584 |
| 139: WNT4 | 1:22318177-22342038 |
| 140: WNT5A | 3:55479112-55489996 |
| 141: WNT5B | 12:1596483-1626640 |
| 142: WNT6 | 2:219432783-219447192 |
| 143: WNT7A | 3:13835085-13896619 |
| 144: WNT7B | 22:44696323-44751395 |
| 145: WNT8A | 5:137447578-137454975 |
| 146: WNT8B | 10:102212788-102233491 |
| 147: WNT9A | 1:226172980-226202222 |
| 148: WNT9B | 17:42265620-42312914 |
PLoS One. 2009; 4(11): e7841
Crampton SP, Wu B, Park EJ, Kim JH, Solomon C, Waterman ML, Hughes CC
BACKGROUND: THE COMPLEXITY OF Wnt signaling LIKELY STEMS FROM TWO SOURCES: multiple pathways emanating from frizzled receptors in response to Wnt binding, and modulation of those pathways and target gene responsiveness by context-dependent signals downstream of growth factor and matrix receptors. Both rac1 and c-jun have recently been implicated in Wnt signaling, however their upstream activators have not been identified. METHODOLOGY/PRINCIPAL FINDINGS: Here we identify the adapter protein Grb2, which is itself an integrator of multiple signaling pathways, as a modifier of beta-catenin-dependent Wnt signaling. Grb2 synergizes with Wnt3A, constitutively active (CA) LRP6, Dvl2 or CA-beta-catenin to drive a LEF/TCF-responsive reporter, and dominant negative (DN) Grb2 or siRNA to Grb2 block Wnt3A-mediated reporter activity. MMP9 is a target of beta-catenin-dependent Wnt signaling, and an MMP9 promoter reporter is also responsive to signals downstream of Grb2. Both a jnk inhibitor and DN-c-jun block transcriptional activation downstream of Dvl2 and Grb2, as does DN-rac1. Integrin ligation by collagen also synergizes with Wnt signaling as does overexpression of Focal Adhesion Kinase (FAK), and this is blocked by DN-Grb2. CONCLUSIONS/SIGNIFICANCE: These data suggest that integrin ligation and FAK activation synergize with Wnt signaling through a Grb2-rac-jnk-c-jun pathway, providing a context-dependent mechanism for modulation of Wnt signaling.
Regulation of protein stability by GSK3 mediated phosphorylation.
Cell Cycle. 2009 Dec 17; 8(24):
Xu C, Kim NG, Gumbiner BM
Glycogen synthase kinase-3 (GSK3) plays important roles in numerous signaling pathways that regulate a variety of cellular processes including cell proliferation, differentiation, apoptosis and embryonic development. In the canonical Wnt signaling pathway, GSK3 phosphorylation mediates proteasomal targeting and degradation of beta-catenin via the destruction complex. We recently reported a biochemical screen that discovered multiple additional protein substrates whose stability is regulated by Wnt signaling and/or GSK3 and these have important implications for Wnt/GSK3 regulation of different cellular processes.(1) In this article, we also present a bio-informatics based screen for proteins whose stability may be controlled by GSK3 and beta-Trcp, the SCF E3 ubiquitin ligase that is responsible for beta-catenin degradation in the Wnt signaling pathway. Furthermore, we review various GSK3 regulated proteolysis substrates described in the literature. We propose that GSK3 phosphorylation dependent proteolysis is a widespread mechanism that the cell employs to regulate a variety of cell processes in response to signals.
Nan Fang Yi Ke Da Xue Xue Bao. 2009 Nov 20; 29(11): 2237-2240
Niu LG, He JJ, Wang K, Zhang W, Zhou C
OBJECTIVE: To investigate the relationship between positive expression of Her2 and abnormal expressions of beta-catenin and E-cadherin and its implications. METHODS: Immunohistochemistry was used to detect the expressions of Her2, beta-catenin and E-cadherin in 147 samples of human breast carcinoma. The expressions of beta-catenin and E-cadherin were also detected in 19 tissues adjacent to the carcinoma and 17 benign breast lesions as controls. RESULTS: In breast carcinoma, positive Her2 expression was associated with lymph node metastasis, advanced clinical stage and negative expression of ER and PR (P<0.05). Abnormal beta-catenin expression was associated with positive lymph node status and high histological grade (P<0.01). Abnormality of E-cadherin expression was related to lymph node metastasis and advanced clinical stage (P<0.05). Abnormal beta-catenin expression was directly correlated with abnormal E-cadherin expression (P<0.01). Her2 positivity showed a direct correlation to abnormal beta-catenin expression (P<0.01), and they cooperated in promoting axillary lymph node metastasis in human breast carcinoma (P<0.01). CONCLUSION: A direct correlation between positive Her2 expression and abnormal beta-catenin expression exists in human breast carcinoma, and positive Her2 expression may have functional interactions with abnormal activation of Wnt/beta-catenin signaling pathway.
Eight Genes Are Highly Associated With Bmd Variation in Postmenopausal Caucasian Women.
Bone. 2009 Nov 13;
Reppe S, Refvem H, Gautvik VT, Olstad OK, Høvring PI, Reinholt FP, Holden M, Frigessi A, Jemtland R, Gautvik KM
Low bone mineral density (BMD) is an important risk factor for skeletal fractures which occur in about 40% of women >/= 50 years in the western world. We describe the transcriptional changes in 84 trans-iliacal bone biopsies associated with BMD variations in postmenopausal females (50 to 86 years), aiming to identify genetic determinants of bone structure. The women were healthy or having a primary osteopenic or osteoporotic status with or without low energy fractures. The total cohort of 91 unrelated women representing a wide range of BMDs, were consecutively registered and submitted to global gene Affymetrix microarray expression analysis or histomorphometry. Among almost 23000 expressed transcripts, a set represented by ACSL3 (acyl-CoA synthetase long-chain family member 3), NIPSNAP3B (nipsnap homolog 3B), DLEU2 (Deleted in lymphocytic leukemia, 2), C1ORF61 (Chromosome 1 open reading frame 61), DKK1 (Dickkopf homolog 1), SOST (Sclerosteosis), ABCA8, (ATP-binding cassette, sub-family A, member 8), and uncharacterized (AFFX-M27830-M-at), was significantly correlated to total hip BMD (5% false discovery rate) explaining 62% of the BMD variation expressed as T-score, 53% when adjusting for the influence of age (Z-score) and 44% when further adjusting for body mass index (BMI). Only SOST was previously associated to BMD, and the majority of the genes have previously not been associated with a bone phenotype. In molecular network analyses, SOST shows a strong, positive correlation with DKK1, both being members of the Wnt signaling pathway. The results provide novel insight in the underlying biology of bone metabolism and osteoporosis which is the ultimate consequence of low BMD.
Am J Physiol Endocrinol Metab. 2009 Nov 17;
Figeac F, Uzan B, Faro M, Chelali N, Portha B, Movassat J
Wnt/beta-catenin signaling is critical for a variety of fondamental cellular processes. Here we investigated the implication of the Wnt/beta-catenin signaling in the in vivo regulation of beta-cell growth and regeneration in normal and diabetic rats. To this aim, TCF7L2, the distal effector of the canonical Wnt pathway was knocked down in groups of normal and diabetic rats, by the use of specific antisense morpholino-oligonucleotides. In other groups of diabetic rats, the Wnt/beta-catenin pathway was activated by the inhibition of its negative regulator: GSK3beta. GSK3beta was inactivated either by LiCl or by anti-GSK3beta oligonucleotides. The beta-cell mass was evaluated by morphometry. beta-cell proliferation was assessed in vivo and in vitro by the BrdU incorporation method. In vivo beta-cell neogenesis was estimated by the evaluation of PDX1-positive and Glut 2-positive ductal cells and the number of beta cells budding from the ducts. We showed that the in vivo disruption of the canonical Wnt pathway resulted in the alteration of normal and compensatory growth of beta cells, mainly through the inhibition of beta-cell proliferation. Conversely, activation of the Wnt pathway through the inhibition of GSK3beta, had significant stimulatory effect on beta-cell regeneration in diabetic rats. In vitro, GSK3beta inactivation resulted in the stimulation of beta-cell proliferation. This was mediated by the stabilization of beta-catenin and the induction of Cyclin D. Taken together, our results demonstrate the involvement of the canonical Wnt signaling in the neonatal regulation of normal and regenerative growth of pancreatic beta cells. Moreover, we provide evidence that activation of this pathway by pharmacological maneuvers can efficiently improve beta-cell regeneration in diabetic rats. These findings might have potential clinical applications in the regenerative therapy of diabetes.
Dishevelled-2 docks and activates Src in a Wnt-dependent manner.
J Cell Sci. 2009 Nov 17;
Yokoyama N, Malbon CC
Wnt3a activates the 'canonical' signaling pathway, stimulating the nuclear accumulation of beta-catenin and activation of Lef/Tcf-sensitive transcription of developmentally important genes. Using totipotent mouse F9 teratocarcinoma cells expressing frizzled-1 (Fz1), we investigated roles of tyrosine kinase activity in Wnt/beta-catenin signaling. Treatment with either genistein or Src family kinase inhibitor PP2 attenuates Wnt3a-stimulated Lef/Tcf transcription activation and primitive endoderm formation. siRNA-induced knockdown of Src likewise attenuates Lef/Tcf transcription and primitive endoderm formation in response to Wnt3a, implicating Src as a positive regulator of Wnt/beta-catenin signaling. We discovered that Src binds dishevelled-2 (Dvl2), a key phosphoprotein in Wnt signaling, at two positions: an SH3-binding domain and a C-terminal domain. The Y18F mutant of Dvl2 attenuates the Wnt3a-stimulated Lef/Tcf-sensitive transcriptional response. Wnt3a stimulates Src docking to Dvl2 and activation of this tyrosine kinase. Activated Src, in turn, enhances Wnt activation of the canonical pathway. We show that Dvl2 and beta-catenin are crucially important substrates for tyrosine phosphorylation in the canonical Wnt/beta-catenin pathway.
Int J Biochem Cell Biol. 2009 Nov 12;
Torre C, Perret C, Colnot S
The liver displays a remarkable phenomenon known as metabolic zonation. Highly specialized hepatocytes fulfill different metabolic functions that depend on their position along the porto-central axis, distinguishing "periportal" hepatocytes from "pericentral" hepatocytes. The mechanisms by which zonation is established have been extensively investigated since its initial discovery. Using murine models with beta-catenin conditional activation or invalidation in the liver, a major role for the Wnt/beta-catenin developmental pathway has been demonstrated in this functional heterogeneity of hepatocytes. Under physiological conditions, this pathway is activated in pericentral hepatocytes. This is partly due to the absence in the pericentral area of adenomatous polyposis coli, a negative regulator also known as the "zonation-keeper" of the liver lobule. The Wnt pathway induces a pericentral genetic program and represses a periportal genetic program in these hepatocytes. In mice with aberrant activation of beta-catenin signaling, Wnt signaling also controls hepatocyte proliferation through a non cell-autonomous mechanism. This pathway therefore controls metabolism and proliferation in liver cells, its role in proliferation being consistent with its involvement in liver cancer. Finally, the hepatic-enriched transcription factor Hnf4 has been shown to play a role in the Wnt-dependent transcription of zonated genes. From these findings, it now appears that the combinatorial interplay of different transcription factors with beta-catenin supports liver metabolic zonation. We propose that genome-wide approaches using chromatin immunoprecipitation will allow to further explore the molecular determinants of beta-catenin dependent liver zonation.
Biochem Biophys Res Commun. 2009 Nov 11;
Santos A, Bakker AD, Zandieh-Doulabi B, de Blieck-Hogervorst JM, Klein-Nulend J
Bone mechanotransduction is vital for skeletal integrity. Osteocytes are thought to be the cellular structures that sense physical forces and transform these signals into a biological response. The Wnt/beta-catenin signaling pathway has been identified as one of the signaling pathways that is activated in response to mechanical loading, but the molecular events that lead to an activation of this pathway in osteocytes are not well understood. We assessed whether nitric oxide, focal adhesion kinase, and/or the phosphatidyl inositol-3 kinase/Akt signaling pathway mediate loading-induced beta-catenin pathway activation in MLO-Y4 osteocytes. We found that mechanical stimulation by pulsating fluid flow (PFF, 0.7+/-0.3 Pa, 5 Hz) for 30 min induced beta-catenin stabilization and activation of the Wnt/beta-catenin signaling pathway. The PFF-induced stabilization of beta-catenin and activation of the beta-catenin signaling pathway was abolished by adding focal kinase inhibitor FAK inhibitor-14 (50 muM), or phosphatidyl inositol-3 kinase inhibitor LY-294002 (50 muM). Addition of nitric oxide synthase inhibitor L-NAME (1.0 mM) also abolished PFF-induced stabilization of beta-catenin. This suggests that mechanical loading activates the beta-catenin signaling pathway by a mechanism involving nitric oxide, focal adhesion kinase, and the Akt signaling pathway. These data provide a framework for understanding the role of beta-catenin in mechanical adaptation of bone.
Cancer Cell Int. 2009 Nov 11; 9(1): 28
Filleur S, Hirsch J, Wille A, Schon M, Sell C, Shearer MH, Nelius T, Wieland I
ABSTRACT: BACKGROUND: The gene encoding integrator complex subunit 6 (INTS6), previously known as deleted in cancer cells 1 (DICE1, OMIM 604331) was found to be frequently affected by allelic deletion and promoter hypermethylation in prostate cancer specimens and cell lines. A missense mutation has been detected in prostate cancer cell line LNCaP. Together, these results suggest INTS6/DICE1 as a putative tumor suppressor gene in prostate cancer. We now examined the growth inhibitory effects of INTS6/DICE1 on prostate cancer cells. RESULTS: Markedly decreased INTS6/DICE1 mRNA levels were detected in prostate cancer cell lines LNCaP, DU145 and PC3 as well as CPTX1532 as compared to NPTX1532, a cell line derived from normal prostate tissue. Ectopic re-expression of INTS6/DICE1 cDNA in androgen-independent PC3 and DU145 cell lines substantially suppressed their ability to form colonies in vitro. This growth inhibition was not due to immediate induction of apoptosis. Rather, prostate cancer cells arrested in G1 phase of the cell cycle. Expression profiling of members of the Wnt signaling pathway revealed up-regulation of several genes including disheveled inhibitor CXXC finger 4 (CXXC4), frizzled homologue 7 (FZD7), transcription factor 7-like 1 (TCF7L1), and down-regulation of cyclin D1. CONCLUSIONS: These results show for the first time a link between INTS6/DICE1 function, cell cycle regulation and cell-cell communication involving members of the Wnt signaling pathway.
The Dawn of Developmental signaling in the Metazoa.
Cold Spring Harb Symp Quant Biol. 2009 Nov 10;
Richards GS, Degnan BM
Intercellular signaling underpins metazoan development by mediating the induction, organization, and cooperation of cells, tissues, and organs. Herein, the origins of the four major signaling pathways used during animal development and differentiation-Wnt, Notch, transforming growth factor-beta (TGF-beta), and Hedgehog-are assessed by comparative analysis of genomes from bilaterians, early branching metazoan phyla (poriferans, placozoans, and cnidarians), and the holozoan sister clade to the animal kingdom, the choanoflagellates. On the basis of the incidence and domain architectures of core pathway ligands, receptors, signal transducers, and transcription factors in representative species of these lineages, it appears that the Notch, Wnt, and TGF-beta pathways are metazoan synapomorphies, whereas the Hedgehog pathway arose in the protoeumetazoan lineage, after its divergence from poriferan and placozoan lineages. Examination of the binding domains and motifs present in signaling pathway components of nonbilaterians reveals cases in which signaling interactions are unlikely to be operating in accordance with bilaterian canons. Overall, this study highlights the stability and antiquity of the core cytosolic components of each pathway, juxtaposed with the more variable and recently evolved molecular interactions taking place at the cell surface.
Cancer stem cells and hepatocellular carcinoma.
Cancer Biol Ther. 2009 Sep; 8(18): 1691-8
Yao Z, Mishra L
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, with a median survival of 6-16 m. Factors responsible for the poor prognosis include late onset diagnosis, underlying cirrhosis and resistance to chemotherapy; 40% of HCCs are clonal and therefore potentially arise from progenitor/stem cells. New insights are provided from several signaling pathways, such as STAT3, NOTCH, hedgehog and transforming growth factor-beta (TGFbeta), which are involved in stem cell renewal, differentiation, survival, and are commonly deregulated in HCC. Control of stem cell proliferation by the TGFbeta, Notch, Wnt and Hedgehog pathways to suppress hepatocellular cancer and to form the endoderm suggest a dual role for this pathway in tumor suppression as well as progression of differentiation from a stem or progenitor stage. This review provides a rationale for detecting and analyzing tumor stem cells as one of the most effective ways to treat cancers such as hepatocellular cancer.
Canonical Wnt signaling negatively regulates platelet function.
Proc Natl Acad Sci U S A. 2009 Nov 9;
Steele BM, Harper MT, Macaulay IC, Morrell CN, Perez-Tamayo A, Foy M, Habas R, Poole AW, Fitzgerald DJ, Maguire PB
Wnts regulate important intracellular signaling events, and dysregulation of the Wnt pathway has been linked to human disease. Here, we uncover numerous Wnt canonical effectors in human platelets where Wnts, their receptors, and downstream signaling components have not been previously described. We demonstrate that the Wnt3a ligand inhibits platelet adhesion, activation, dense granule secretion, and aggregation. Wnt3a also altered platelet shape change and inhibited the activation of the small GTPase RhoA. In addition, we found the Wnt-beta-catenin signaling pathway to be functional in platelets. Finally, disruption of the Wnt Frizzled 6 receptor in the mouse resulted in a hyperactivatory platelet phenotype and a reduced sensitivity to Wnt3a. Taken together our studies reveal a novel functional role for Wnt signaling in regulating anucleate platelet function and may provide a tractable target for future antiplatelet therapy.
Biochem Biophys Res Commun. 2009 Nov 10;
Du R, Huang C, Bi Q, Zhai Y, Xia L, Liu J, Sun S, Fan D
Upregulated gene 11 (URG11), recently identified as a new HBx-upregulated gene that may activate beta-catenin and Wnt signaling, was found to be upregulated in a human tubule cell line under low oxygen. Here, we investigated the potential role of URG11 in hypoxia-induced renal tubular epithelial-to-mesenchymal (EMT). Overexpression of URG11 in a human proximal tubule cell line (HK2) promoted a mesenchymal phenotype accompanied by reduced expression of the epithelial marker E-cadherin and increased expression of the mesenchymal markers vimentin and alpha-SMA, while URG11 knockdown by siRNA effectively reversed hypoxia-induced EMT. URG11 promoted the expression of beta-catenin and increased its nuclear accumulation under normoxic conditions through transactivation of the beta-catenin promoter. This in turn upregulated beta-catenin/T-cell factor (TCF) and its downstream effector genes, vimentin, and alpha-SMA. In vivo, strong expression of URG11 was observed in the tubular epithelia of 5/6-nephrectomized rats, and a Western blot analysis demonstrated a close correlation between HIF-1alpha and URG11 protein levels. Altogether, our results indicate that URG11 mediates hypoxia-induced EMT through the suppression of E-cadherin and the activation of the beta-catenin/TCF pathway.
Mod Pathol. 2009 Nov 6;
Kurihara S, Oda Y, Ohishi Y, Kaneki E, Kobayashi H, Wake N, Tsuneyoshi M
Aberrant activation of the Wnt signaling pathway has been implicated in tumorigenesis of a wide range of tumors, including colorectal cancer. Regarding endometrial stromal tumors and related high-grade sarcomas, there have been some reports regarding nuclear accumulation of beta-catenin. To clarify the function of the aberrant Wnt signaling pathway in these tumors, we searched for mutations of the CTNNB1 (beta-catenin) gene and APC gene by PCR direct sequencing and analyzed the methylation status of SFRP genes. We also examined overexpression of cyclin D1 and MMP-7, which are direct target genes of beta-catenin. Eight endometrial stromal nodules, 16 low-grade endometrial stromal sarcomas, and 13 undifferentiated endometrial sarcomas were examined. PCR and direct sequencing revealed no mutation of the beta-catenin gene or the APC gene. Concerning the promoter methylation status of SFRP genes, methylation-specific PCR revealed no significant difference between the group with nuclear beta-catenin expression and that without nuclear beta-catenin expression. Immunohistochemistry revealed overexpression of cyclin D1 in 2 out of 8 endometrial stromal nodules, 1 out of 17 low-grade endometrial stromal sarcomas, and 6 out of 13 undifferentiated endometrial sarcomas, and these 6 undifferentiated endometrial sarcomas simultaneously expressed nuclear beta-catenin. Interestingly, all six undifferentiated endometrial sarcoma cases with cyclin D1 overexpression histologically featured rather uniform nuclei. In contrast, the six cases of undifferentiated endometrial sarcoma with highly pleomorphic nuclei were all negative for cyclin D1. In conclusion, among endometrial stromal tumors and related sarcomas, undifferentiated endometrial sarcomas featuring uniform nuclei were characterized by frequent coincident expression of beta-catenin and cyclin D1. This finding raises the possibility that cyclin D1 is upregulated by beta-catenin in these high-grade sarcomas previously called high-grade endometrial stromal sarcoma.Modern Pathology advance online publication, 6 November 2009; doi:10.1038/modpathol.2009.162.
Hum Mol Genet. 2009 Nov 6;
Kim JK, Kim E, Baek IC, Kim BK, Cho AR, Kim TY, Song CW, Seong JK, Yoon JB, Stenn KS, Parimoo S, Yoon SK
Marie Unna hereditary hypotrichosis (MUHH) is a rare autosomal dominant hair disorder. Through the study of a mouse model, we identified a mutation in the 5'-untranslated region of the hairless (HR) gene in patients with MUHH in a Caucasian family. The corresponding mutation, named 'hairpoor', was found in mutant mice that were generated through N-ethyl-N-nitrosourea mutagenesis. Hairpoor mouse mutants display partial hair loss at an early age and progress to near alopecia, which resembles the MUHH phenotype. This mutation conferred overexpression of HR through translational derepression and, in turn, decreased the expression of Sfrp2, an inhibitor of the Wnt signaling pathway. This study indicates that the gain in function of HR also results in alopecia, as seen with the loss of function of HR, via abnormal upregulation of the Wnt signaling pathway.
HPV16 E6 augments Wnt signaling in an E6AP-dependent manner.
Virology. 2009 Nov 5;
Lichtig H, Gilboa DA, Jackman A, Gonen P, Levav-Cohen Y, Haupt Y, Sherman L
In this study we investigated the effect of HPV16 E6 on the Wnt/beta-catenin oncogenic signaling pathway. Luciferase reporter assays indicated that ectopically expressed E6 significantly augmented the Wnt/beta-catenin/TCF-dependent signaling response in a dose-dependent manner. This activity was independent of the ability of E6 to target p53 for degradation or bind to the PDZ-containing E6 targets. Epistasis experiments suggested that the stimulatory effect is independent of GSK3beta or APC. Coexpression, half-life determination, cell fractionation and immunofluorescence analyses indicated that E6 did not alter the expression levels, stability or cellular distribution of beta-catenin. Further experiments using E6 mutants defective for E6AP binding and E6AP knockdown cells indicated the absolute requirement of the ubiquitin ligase E6AP for enhancement of the Wnt signal by E6. Thus, this study suggests a role for the E6/E6AP complex in augmentation of the Wnt signaling pathway which may contribute to HPV induced carcinogenesis.
Targeting regulation of ABC efflux transporters in brain diseases: A novel therapeutic approach.
Pharmacol Ther. 2009 Nov 5;
Potschka H
Blood-brain barrier efflux transporters limit the brain penetration and efficacy of various central nervous system drugs. In several CNS diseases, therapy- or pathophysiology-associated transcriptional activation of efflux transporters further strengthens the barrier function. Targeting the regulatory pathways that drive efflux transporter expression in different diseases represents an intriguing approach for prevention of these events thereby promoting delivery to the brain and enhancing or restoring drug efficacy. In particular, the approach holds the promise to preserve basal transporter expression and activity, which is of specific relevance in view of the protective function of efflux transport. The elucidation of the signaling cascades involved in transporter regulation is a major presupposition for the development of preventive strategies. Orphan nuclear receptors as well as the Wnt/beta-catenin signaling pathway have been implicated in drug-induced changes in transporter expression. Targeting these xenobiotic sensors is therefore discussed as a means to optimize brain delivery and therapeutic outcome. Relevant progress has also been made with the identification of key signaling events that drive P-glycoprotein expression in response to pathophysiological mechanisms. In the epileptic brain, complex signaling events involving cyclooxygenase-2 activity trigger P-glycoprotein expression in response to glutamate release and activation of endothelial NMDA receptors. Moreover, reactive oxygen species and inflammatory cytokines have been identified as regulatory factors which might affect P-glycoprotein in several CNS diseases. Recent data substantiated several interesting targets in the respective signaling cascades thereby rendering a basis for the ongoing development of innovative approaches to optimize central nervous system drug brain penetration and efficacy.
Screening for beneficial effects of oral intake of sweet corn by DNA microarray analysis.
J Food Sci. 2009 Sep; 74(7): H197-203
Tokuji Y, Akiyama K, Yunoki K, Kinoshita M, Sasaki K, Kobayashi H, Wada M, Ohnishi M
To identify novel functions of the oral intake of sweet corn, we performed DNA microarray analysis of the livers of sweet corn-fed mice. Functional annotation clustering 1600 genes with expression levels that were affected (more than 1.5-fold change) by dietary sweet corn indicated that both cell proliferation and programmed cell death were modulated by sweet corn intake. In the Wnt signaling pathway, which is involved in cell proliferation, the levels of Jun and beta-catenin expression were downregulated by dietary sweet corn. The mRNA levels of Rb and p53, negative regulators of the cell cycle, were increased in mice fed with sweet corn. Dietary corn upregulated expression levels of genes that regulate apoptosis positively (for example, BOK, BID, CASP4). These results suggested that sweet corn is a valuable food for suppressing cancer. Oral administration of sweet corn inhibited tumor growth (36.6% reduce in tumor weight, P < 0.05) in mice inoculated with Ehrlich tumor cells.
Am J Pathol. 2009 Nov 5;
Chen Y, Hu Y, Zhou T, Zhou KK, Mott R, Wu M, Boulton M, Lyons TJ, Gao G, Ma JX
Although Wnt signaling is known to mediate multiple biological and pathological processes, its association with diabetic retinopathy (DR) has not been established. Here we show that retinal levels and nuclear translocation of beta-catenin, a key effector in the canonical Wnt pathway, were increased in humans with DR and in three DR models. Retinal levels of low-density lipoprotein receptor-related proteins 5 and 6, coreceptors of Wnts, were also elevated in the DR models. The high glucose-induced activation of beta-catenin was attenuated by aminoguanidine, suggesting that oxidative stress is a direct cause for the Wnt pathway activation in diabetes. Indeed, Dickkopf homolog 1, a specific inhibitor of the Wnt pathway, ameliorated retinal inflammation, vascular leakage, and retinal neovascularization in the DR models. Dickkopf homolog 1 also blocked the generation of reactive oxygen species induced by high glucose, suggesting that Wnt signaling contributes to the oxidative stress in diabetes. These observations indicate that the Wnt pathway plays a pathogenic role in DR and represents a novel therapeutic target.
Mol Syst Biol. 2009; 5: 315
Miller BW, Lau G, Grouios C, Mollica E, Barrios-Rodiles M, Liu Y, Datti A, Morris Q, Wrana JL, Attisano L
Large-scale proteomic approaches have been used to study signaling pathways. However, identification of biologically relevant hits from a single screen remains challenging due to limitations inherent in each individual approach. To overcome these limitations, we implemented an integrated, multi-dimensional approach and used it to identify Wnt pathway modulators. The LUMIER protein-protein interaction mapping method was used in conjunction with two functional screens that examined the effect of overexpression and siRNA-mediated gene knockdown on Wnt signaling. Meta-analysis of the three data sets yielded a combined pathway score (CPS) for each tested component, a value reflecting the likelihood that an individual protein is a Wnt pathway regulator. We characterized the role of two proteins with high CPSs, Ube2m and Nkd1. We show that Ube2m interacts with and modulates beta-catenin stability, and that the antagonistic effect of Nkd1 on Wnt signaling requires interaction with Axin, itself a negative pathway regulator. Thus, integrated physical and functional mapping in mammalian cells can identify signaling components with high confidence and provides unanticipated insights into pathway regulators.