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1 pp. Wnt Wnt Wnt Wnt β- PCP Ca Wnt Wnt Wnt Wnt Wnt Wingless Wg int- Wingless int Wnt Wnt Wnt β- β- planar cell polarity PCP PCP Ca Ca Wnt β- β- Wnt Wnt signaling; its abnormalities and diseases Akira Kikuchi Department of Biochemistry, School of Biomedical Sciences, Hiroshima University,, Kasumi, Minami-ku, Hiroshima, Japan β- Wnt β- β- PCP PCP Wnt Frizzled Fz Dishevelled DvlRho G GTP Rho Rho kinase Jun Jun-Nterminal kinase JNK Ca Wnt Ca Ca calmodulindependent protein kinase CaMK C protein kinase C PKC β- β- Wnt Wnt

2 Wnt Wnt β- PCP Ca CaMK, Ca calmodulin-dependent kinase; Fz, Frizzled, GSK- β; glycogen synthase kinase- β; JNK, c-jun N-terminal kinase; LRP, low density lipoprotein receptorrelated protein ; PKC, protein kinase C; Tcf Lef, T-cell factor lymphoid enhancer factor. C MG Wnt Wnt a Wnt a Wnt a Wnt Wnt Wnt Wnt β- Wnt β- Wnt a Rho Wnt a β- Wnt Wnt Fz Fz low density lipoprotein receptor-related protein LRPLRP receptor tyrosine kinase-like orphan receptor Rorrelated tyrosine kinase orphan receptor Ryk β- Fz LRP LRP Wnt a Fz Ror β- Wnt Wnt Wnt β- adenomatous polyposis coli APC LRP β- Wnt Wnt Wnt Wnt β- Wnt β- T cell factor Lymphocyte enhancing factor Tcf Lefcyclin D c-myc Wnt β- β- APC - β glycogen synthase kinase- β GSK- β Axin Axin α casein kinase α CK α GSK- β

3 Wnt Wnt CBP, cyclic AMP responsive element binding protein CREB binding protein; sfrp, soluble Frizzled related protein. Wnt Wnt Wnt β- Axin gate keeper gene Axin β- β- cyclin D c-myc β- CK α GSK- β Fbw β- CK α GSK- β β- APC familiar adenomatous polyposis coli FAP APC β- β- FAP APC FAP APC C APC β- Axin β- β-

4 Axin Axin Axil conductin Axin Axin Axin Axin APC β- GSK- β β- β- β- β- Wnt a β- Wnt a Dukes B Wnt a Wnt a B Wnt a Wnt a Wnt a Wnt a Wnt a diffuse-scattered type Wnt a Wnt a Wnt a Rac Wnt a γ γ Wnt a γ Wnt a Wnt a Wnt a Wnt a Wnt Wnt Wnt Dvl Wnt Wnt Wnt β- Wnt Dickkopf DKK Wnt Fz q Fz GSK- β CAA n GSK- β GSK- β GSK- β q GSK- β T C Wnt GSK- VPA GSK- β- GSK- Wnt GSK- β- GSK- Wnt

5 GSK- GSK- GSK- βaβ APP PS PS Aβ PS GSK- β- β- PS β- PS β- AMP CREBCBP β- PS β- GSK- APP Aβ Aβ β- Wnt a Aβ Wnt Dkk β- Dvl β- PKC JNK APP β- Aβ ApoE ε E ε ε ApoE ApoE LRP LRP Aβ Wnt LRP ApoE LRP ApoE Wingless Wnt ApoE Wnt LRP β- Wnt Wnt A β- Dkk Wnt receptor activator of NF-κB ligand RANKL osteoprotegerin OPG β- LRP LRP Wnt soluble Fzrelated protein sfrp osteoporosis-pseudoglioma syndrome OPPGLRP OPPG β- sfrp sfrp Wnt Wnt RA RA Wnt Wnt a Fz Wnt a IL- IL- IL- Wnt a RA RANKL Wnt JNK pro-matrix metaroprotease pro-mmp RA Wnt Wnt

6 Wnt A β- Dkk Wnt RANKL Dkk, Dickkopf ; Sost, Sclerostin; OPG, osteoprotegerin; RANKL, receptor activator of NF-κB ligand. B β- ES Fz RANKL MMP Wnt Wnt β- Bβ- ES Wnt a ES Wnt a ES Wnt β- JNK Fz Fz

7 Dkk Dvl β- β-β- β- β- Wnt Fz Wnt b Wnt b Dvl β- sfrp infarct rupture Wnt Dvl Wnt LRP EGF LRP Wnt LRP β- Wnt Wnt b Wnt Wnt Wnt a β- β Wnt β- TCF L TCF TCF L TCF L TCF L mrna TCF L mrna Tcf β- glucagon-like peptide GLP GLP β Wnt b Wnt b PPARG peroxisome proliferatorsactivated receptor γ APM adiponectin Wnt b Wnt a Wnt a CaMK PPARγ Wnt a Wnt b β- Wnt Wnt WntWntFz β- β- β- Wnt FEVR FEVR Fz LRP Fz Fz Fz Fz Wnt FEVR

8 OPPG LRP β- FEVR Fz Norrin Norrin FEVR Wnt autosomal dominant polycystic kidney disease ADPKD PKD PKD β- PKD Wnt Wnt β- Wnt Wnt Wnt Wnt Wnt Wnt β- Wnt Wnt NSAID NSAID NSAID COX FAP Wnt AMP β- COX β- NSAID COX sulindac sulphide FAP β- COX NSAID Wnt APC β- Axin β- Wnt Fz Dvl sfrp Wnt inhibitory factor WIF Wnt Wnt Wnt Wnt Wnt APC β- Axin Wnt sfrp β- Wnt Wnt in vivo β- β- Tcf β- β- E- APC Axin β- Tcf β- PKF- PKF- CGP β- Tcf hot spot β- Tcf in silico β- Tcf PNU- β- CBP BCL pygopus Wnt ICG- CBP

9 β- PKF- ELISA β- Tcf β- Tcf PKF- ELISA β- Tcf β- Tcf CGP ELISA β- Tcf β- Tcf PNU- β- Tcf ICG- β- Tcf β- CBP β- CBP β- Tcf survivin Wnt Wnt in vitro Wnt ES Wnt ES pluripotency ES ES ES APC ES in vitro ES leukemia inhibitory factor LIF APC ES β- β- ES APC ES ES Tcf Nanog Oct Sox ES Tcf Nanog Oct Sox ES ES β- GSK- BIO Wnt a ES LIF fibroblast growth factor FGF ES Nanog Oct Klf c-myc ips c-myc β- Tcf c-myc Wnt a ips β- ES ips Wnt niche Wnt Tcf Lef

10 β- Wnt a β- T B HoxB β- HoxB niche Dkk β- β- β- niche Tcf β- β- Tcf Lgr G Tcf EphB ephrinb β- ephrinb EphB EphB β- ephrinb EphB Wnt Wnt Wnt Wnt Wnt β- Tcf Wnt Wnt Wnt Wnt Wnt Logan, C.Y. & Nusse, R.Annu. Rev. Cell Dev. Biol.,, Kikuchi, A., Yamamoto, H., & Kishida, S.Cell. Signal.,, Veeman, M.T., Axelrod, J.D., & Moon, R.T.Dev. Cell,,

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CRA3689A

CRA3689A AVIC-DRZ90 AVIC-DRZ80 2 3 4 5 66 7 88 9 10 10 10 11 12 13 14 15 1 1 0 OPEN ANGLE REMOTE WIDE SET UP AVIC-DRZ90 SOURCE OFF AV CONTROL MIC 2 16 17 1 2 0 0 1 AVIC-DRZ90 2 3 4 OPEN ANGLE REMOTE SOURCE OFF