title: Gbetagamma activates GSK3 to promote LRP6-mediated beta-catenin transcriptional activity.
abstract: Evidence from Drosophila and cultured cell studies supports a role for heterotrimeric guanosine triphosphate-binding proteins (G proteins) in Wnt signaling. Wnt inhibits the degradation of the transcriptional regulator beta-catenin. We screened the alpha and betagamma subunits of major families of G proteins in a Xenopus egg extract system that reconstitutes beta-catenin degradation. We found that Galpha(o), Galpha(q), Galpha(i2), and Gbetagamma inhibited beta-catenin degradation. Gbeta(1)gamma(2) promoted the phosphorylation and activation of the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) by recruiting glycogen synthase kinase 3 (GSK3) to the membrane and enhancing its kinase activity. In both a reporter gene assay and an in vivo assay, c-betaARK (C-terminal domain of beta-adrenergic receptor kinase), an inhibitor of Gbetagamma, blocked LRP6 activity. Several components of the Wnt-beta-catenin pathway formed a complex: Gbeta(1)gamma(2), LRP6, GSK3, axin, and dishevelled. We propose that free Gbetagamma and Galpha subunits, released from activated G proteins, act cooperatively to inhibit beta-catenin degradation and activate beta-catenin-mediated transcription.
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Jernigan
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Cselenyi
authors.forename: Curtis A
authors.initials: CA
authors.lastname: Thorne
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Hanson
authors.forename: Emilios
authors.initials: E
authors.lastname: Tahinci
authors.forename: Nicole
authors.initials: N
authors.lastname: Hajicek
authors.forename: William M
authors.initials: WM
authors.lastname: Oldham
authors.forename: Laura A
authors.initials: LA
authors.lastname: Lee
authors.forename: Heidi E
authors.initials: HE
authors.lastname: Hamm
authors.forename: John R
authors.initials: JR
authors.lastname: Hepler
authors.forename: Tohru
authors.initials: T
authors.lastname: Kozasa
authors.forename: Maurine E
authors.initials: ME
authors.lastname: Linder
authors.forename: Ethan
authors.initials: E
authors.lastname: Lee
mesh_terms: D000818:Animals; D004331:Drosophila melanogaster; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000096:biosynthesis* / Q000235:genetics; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D051552:beta-Adrenergic Receptor Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051153:Wnt Proteins; D051176:beta Catenin; D051552:beta-Adrenergic Receptor Kinases; D038362:Glycogen Synthase Kinase 3
references.citation: Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):8032-7
references.pmid: 18509060
references.citation: Dev Cell. 2009 Jul;17(1):9-26
references.pmid: 19619488
references.citation: PLoS One. 2009;4(3):e4926
references.pmid: 19293931
references.citation: Methods Enzymol. 1994;237:146-64
references.pmid: 7934993
references.citation: J Cell Biol. 1998 Mar 9;140(5):1125-36
references.pmid: 9490725
references.citation: Methods Enzymol. 1991;195:202-15
references.pmid: 1903487
references.citation: Cell. 2005 Jan 14;120(1):111-22
references.pmid: 15652486
references.citation: Mol Endocrinol. 2007 Dec;21(12):3028-38
references.pmid: 17717075
references.citation: Development. 2010 Apr;137(8):1327-37
references.pmid: 20332150
references.citation: Biochemistry. 1974 May 21;13(11):2438-44
references.pmid: 4545509
references.citation: Cell Mol Life Sci. 2008 Jul;65(14):2191-214
references.pmid: 18488142
references.citation: J Biol Chem. 1984 Nov 25;259(22):13806-13
references.pmid: 6438083
references.citation: EMBO J. 2001 Feb 15;20(4):767-76
references.pmid: 11179221
references.citation: J Cell Biol. 1987 Nov;105(5):2191-201
references.pmid: 3680377
references.citation: Mol Cell. 2004 Jan 16;13(1):149-56
references.pmid: 14731402
references.citation: Biochem Biophys Res Commun. 2009 May 1;382(2):365-9
references.pmid: 19285033
references.citation: J Biol Chem. 1994 Feb 11;269(6):4388-95
references.pmid: 8308009
references.citation: Curr Biol. 1996 Nov 1;6(11):1456-67
references.pmid: 8939601
references.citation: Nat Methods. 2005 Mar;2(3):177-84
references.pmid: 15782186
references.citation: J Biol Chem. 1990 May 15;265(14):8243-51
references.pmid: 2159473
references.citation: Nature. 2000 Sep 28;407(6803):530-5
references.pmid: 11029007
references.citation: Methods Cell Biol. 1991;36:657-62
references.pmid: 1811156
references.citation: Methods Enzymol. 1994;237:191-212
references.pmid: 7934997
references.citation: Nat Cell Biol. 2006 Apr;8(4):348-57
references.pmid: 16547521
references.citation: Nature. 2005 Dec 8;438(7069):867-72
references.pmid: 16341016
references.citation: Mol Cell. 2000 Mar;5(3):523-32
references.pmid: 10882137
references.citation: Genes Dev. 2008 Nov 1;22(21):2968-79
references.pmid: 18981475
references.citation: Dev Dyn. 2010 Jan;239(1):168-83
references.pmid: 19705439
references.citation: Biochemistry. 2005 Aug 9;44(31):10593-604
references.pmid: 16060668
references.citation: J Biol Chem. 2007 Sep 7;282(36):26490-502
references.pmid: 17595165
references.citation: J Biol Chem. 2002 Jan 25;277(4):2614-9
references.pmid: 11706038
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9493-8
references.pmid: 15983374
references.citation: J Biol Chem. 1994 Feb 25;269(8):6193-7
references.pmid: 8119963
references.citation: J Cell Biol. 1994 May;125(4):705-19
references.pmid: 8188741
references.citation: Biochemistry. 2006 Jan 10;45(1):167-74
references.pmid: 16388592
references.citation: J Cell Biol. 1987 Nov;105(5):2203-15
references.pmid: 2890645
references.citation: Philos Trans R Soc Lond B Biol Sci. 1987 Dec 15;317(1187):483-94
references.pmid: 2894683
references.citation: J Biol Chem. 1997 Dec 12;272(50):31576-81
references.pmid: 9395495
references.citation: Science. 1998 May 22;280(5367):1271-4
references.pmid: 9596582
references.citation: PLoS One. 2008;3(12):e4046
references.pmid: 19107203
references.citation: FEBS Lett. 2000 Jun 2;474(2-3):189-94
references.pmid: 10838083
references.citation: Exp Mol Med. 2009 Oct 31;41(10):695-706
references.pmid: 19561403
references.citation: J Biol Chem. 1993 Jul 5;268(19):14367-75
references.pmid: 8314796
references.citation: J Biol Chem. 2006 Apr 14;281(15):10250-62
references.pmid: 16446365
references.citation: Science. 2001 Jun 1;292(5522):1718-22
references.pmid: 11387477
references.citation: Science. 2007 Jun 15;316(5831):1619-22
references.pmid: 17569865
references.citation: Development. 2008 Jan;135(2):367-75
references.pmid: 18077588
references.citation: Nature. 2005 Dec 8;438(7069):873-7
references.pmid: 16341017
references.citation: Science. 1993 Jul 9;261(5118):218-21
references.pmid: 8327893