title: The terminal region of beta-catenin promotes stability by shielding the Armadillo repeats from the axin-scaffold destruction complex.
abstract: Post-translational stabilization of beta-catenin is a key step in Wnt signaling, but the features of beta-catenin required for stabilization are incompletely understood. We show that forms of beta-catenin lacking the unstructured C-terminal domain (CTD) show faster turnover than full-length or minimally truncated beta-catenins. Mutants that exhibit faster turnover show enhanced association with axin in co-transfected cells, and excess CTD polypeptide can compete binding of the beta-catenin armadillo (arm) repeat domain to axin in vitro, indicating that the CTD may restrict beta-catenin binding to the axin-scaffold complex. Fluorescent resonance energy transmission (FRET) analysis of cyan fluorescent protein (CFP)-arm-CTD-yellow fluorescent protein beta-catenin reveals that the CTD of beta-catenin can become spatially close to the N-terminal arm repeat region of beta-catenin. FRET activity is strongly diminished by the coexpression of beta-catenin binding partners, indicating that an unliganded groove is absolutely required for an orientation that allows FRET. Amino acids 733-759 are critical for beta-catenin FRET activity and stability. These data indicate that an N-terminal orientation of the CTD is required for beta-catenin stabilization and suggest a model where the CTD extends toward the N-terminal arm repeats, shielding these repeats from the beta-catenin destruction complex.
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
authors.forename: Rigen
authors.initials: R
authors.lastname: Mo
authors.affiliation: Cellular and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
authors.forename: Teng-Leong
authors.initials: TL
authors.lastname: Chew
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Integrated Graduate Program in the Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
authors.forename: Meghan T
authors.initials: MT
authors.lastname: Maher
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19106.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Bellipanni
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19106.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Weinberg
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611. Electronic address: c-gottardi@northwestern.edu.
authors.forename: Cara J
authors.initials: CJ
authors.lastname: Gottardi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D060466:Axin Protein; D002460:Cell Line; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020798:Two-Hybrid System Techniques; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D060466:Axin Protein; D012097:Repressor Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
references.citation: Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):8032-7
references.pmid: 18509060
references.citation: J Cell Biol. 2002 Feb 4;156(3):543-53
references.pmid: 11815633
references.citation: J Cell Biol. 2001 Sep 3;154(5):983-93
references.pmid: 11524435
references.citation: Cell. 2005 Jun 3;121(5):761-72
references.pmid: 15935762
references.citation: J Biol Chem. 2006 Jan 13;281(2):1027-38
references.pmid: 16293619
references.citation: Exp Cell Res. 2000 Mar 15;255(2):207-20
references.pmid: 10694436
references.citation: Genes Dev. 2000 Jul 15;14(14):1741-9
references.pmid: 10898789
references.citation: Genes Dev. 2006 Jun 1;20(11):1394-404
references.pmid: 16751178
references.citation: Genetics. 1999 Sep;153(1):319-32
references.pmid: 10471715
references.citation: Nat Cell Biol. 2001 Sep;3(9):793-801
references.pmid: 11533658
references.citation: Genes Dev. 1989 Jan;3(1):96-113
references.pmid: 2707602
references.citation: J Biol Chem. 2002 Aug 30;277(35):31541-50
references.pmid: 12077140
references.citation: EMBO J. 2000 Aug 1;19(15):3978-89
references.pmid: 10921879
references.citation: Curr Biol. 1998 May 21;8(11):622-32
references.pmid: 9635189
references.citation: J Biol Chem. 2003 Oct 3;278(40):38758-64
references.pmid: 12874278
references.citation: Science. 2002 Jul 19;297(5580):365-9
references.pmid: 12130776
references.citation: J Biol Chem. 2001 Oct 19;276(42):39037-45
references.pmid: 11487578
references.citation: Biochem Biophys Res Commun. 2000 Apr 21;270(3):903-9
references.pmid: 10772923
references.citation: J Cell Biol. 2009 Jul 27;186(2):219-28
references.pmid: 19620634
references.citation: Mol Cell. 2002 Sep;10(3):573-84
references.pmid: 12408825
references.citation: J Cell Biol. 2004 Oct 25;167(2):339-49
references.pmid: 15492040
references.citation: PLoS One. 2009;4(3):e4926
references.pmid: 19293931
references.citation: Genes Dev. 2006 Mar 1;20(5):586-600
references.pmid: 16510874
references.citation: J Neurosci. 2002 Feb 1;22(3):757-65
references.pmid: 11826105
references.citation: Mol Cell. 2004 Aug 27;15(4):523-33
references.pmid: 15327769
references.citation: J Cell Biol. 2007 Jan 1;176(1):51-63
references.pmid: 17200416
references.citation: Am J Physiol Cell Physiol. 2004 Apr;286(4):C747-56
references.pmid: 14613891
references.citation: Structure. 2008 Mar;16(3):478-87
references.pmid: 18334222
references.citation: Curr Biol. 2001 Oct 2;11(19):R792-4
references.pmid: 11591340
references.citation: Science. 1996 May 17;272(5264):1023-6
references.pmid: 8638126
references.citation: Cell. 2002 Mar 22;108(6):837-47
references.pmid: 11955436
references.citation: Development. 2006 Apr;133(7):1299-309
references.pmid: 16510506
references.citation: Genes Dev. 2003 Nov 15;17(22):2753-64
references.pmid: 14600025
references.citation: Mol Cell. 2004 Aug 27;15(4):511-21
references.pmid: 15327768
references.citation: EMBO J. 2007 Mar 21;26(6):1511-21
references.pmid: 17318175
references.citation: Genes Dev. 1996 Jun 15;10(12):1443-54
references.pmid: 8666229
references.citation: EMBO J. 2003 Feb 3;22(3):494-501
references.pmid: 12554650
references.citation: Development. 2000 Sep;127(18):3899-911
references.pmid: 10952888
references.citation: Mol Cell. 2008 Dec 5;32(5):652-61
references.pmid: 19061640
references.citation: Biochem Biophys Res Commun. 1999 Dec 9;266(1):28-35
references.pmid: 10581160
references.citation: Physiology (Bethesda). 2007 Oct;22:303-9
references.pmid: 17928543
references.citation: Mol Cell. 2006 Mar 17;21(6):799-809
references.pmid: 16543149
references.citation: PLoS One. 2008;3(12):e4046
references.pmid: 19107203
references.citation: Cell. 1997 Sep 5;90(5):871-82
references.pmid: 9298899
references.citation: Dev Biol. 2000 Jul 15;223(2):441-8
references.pmid: 10882528
references.citation: Cell. 2000 Dec 8;103(6):885-96
references.pmid: 11136974
references.citation: Nat Struct Biol. 2000 Sep;7(9):800-7
references.pmid: 10966653
references.citation: Curr Biol. 1999 Feb 25;9(4):207-10
references.pmid: 10074433
references.citation: Cell. 2006 Oct 6;127(1):139-55
references.pmid: 17018282
references.citation: Development. 1994 Feb;120(2):369-80
references.pmid: 8149915
references.citation: Science. 2005 May 20;308(5725):1181-4
references.pmid: 15905404
references.citation: Neuron. 2007 Feb 1;53(3):387-97
references.pmid: 17270735
references.citation: Genes Dev. 1999 Jul 15;13(14):1768-73
references.pmid: 10421629
references.citation: Cell. 2001 May 4;105(3):391-402
references.pmid: 11348595
references.citation: EMBO Rep. 2002 Jan;3(1):63-8
references.pmid: 11751573
references.citation: Structure. 2008 Mar;16(3):336-8
references.pmid: 18334207