title: Leucine-rich repeat-containing G-protein coupled receptor 5/GPR49 activates G12/13-Rho GTPase pathway.
abstract: Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5/GPR49) is highly expressed in adult stem cells of various tissues, such as intestine, hair follicles, and stomach. LGR5 is also overexpressed in some colon and ovarian tumors. Recent reports show that R-spondin (RSPO) family ligands bind to and activate LGR5, enhancing canonical Wnt signaling via the interaction with LRP5/6 and Frizzled. The identity of heterotrimeric G-proteins coupled to LGR5, however, remains unclear. Here, we show that Rho GTPase is a downstream target of LGR5. Overexpression of LGR5 induced SRF-RE luciferase activity, a reporter of Rho signaling. RSPOs, ligands for LGR4, LGR5, and LGR6, however, did not induce SRF-RE reporter activity in the presence of LGR5. Consistently, LGR5-induced activity of the SRF-RE reporter was inhibited by Rho inhibitor C3 transferase and RhoA N19 mutant, and knockdown of Gα12/13 genes blocked the reporter activity induced by LGR5. In addition, focal adhesion kinase, NF-κB and c-fos, targets of Rho GTPase, were shown to be regulated by LGR5. Here, we have demonstrated, for the first time, that LGR5 is coupled to the Rho pathway through G12/13 signaling.
authors.affiliation: Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongwon, 363-883, Korea.
authors.forename: Mi So
authors.initials: MS
authors.lastname: Kwon
authors.forename: Bi-oh
authors.initials: BO
authors.lastname: Park
authors.forename: Ho Min
authors.initials: HM
authors.lastname: Kim
authors.forename: Sunhong
authors.initials: S
authors.lastname: Kim
mesh_terms: D000328:Adult; D002460:Cell Line; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019699:Thrombospondins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase; D000098907:R-Spondins
chemical_list: D044365:GTP-Binding Protein alpha Subunits, G12-G13; D017346:Protein Serine-Threonine Kinases; D016760:Proto-Oncogene Proteins c-fos; D043562:Receptors, G-Protein-Coupled; D019699:Thrombospondins; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000097782:NF-kappaB-Inducing Kinase; C411562:LGR4 protein, human; C116884:LGR5 protein, human; C417544:LGR6 protein, human; C503243:RSPO1 protein, human; D000098907:R-Spondins; C066737:RHOA protein, human
references.citation: Mol Cell Biol. 2004 Nov;24(22):9736-43
references.pmid: 15509778
references.citation: Oncogene. 2006 Apr 6;25(15):2234-44
references.pmid: 16301993
references.citation: Mol Endocrinol. 2000 Aug;14(8):1257-71
references.pmid: 10935549
references.citation: J Biol Chem. 2004 Oct 1;279(40):42331-6
references.pmid: 15277528
references.citation: J Biol Chem. 2008 Jul 18;283(29):20330-41
references.pmid: 18445595
references.citation: Annu Rev Cell Dev Biol. 2005;21:247-69
references.pmid: 16212495
references.citation: J Biol Chem. 2001 Dec 7;276(49):45979-87
references.pmid: 11590141
references.citation: Gastroenterology. 2003 May;124(5):1180-7
references.pmid: 12730857
references.citation: Mol Cells. 2012 Feb;33(2):151-62
references.pmid: 22286231
references.citation: Oncogene. 1993 May;8(5):1285-92
references.pmid: 8479750
references.citation: Semin Cancer Biol. 2003 Apr;13(2):107-14
references.pmid: 12654254
references.citation: PLoS One. 2012;7(7):e40976
references.pmid: 22815884
references.citation: Mol Cell Biol. 2003 Sep;23(18):6597-608
references.pmid: 12944485
references.citation: Dev Cell. 2004 Apr;6(4):483-95
references.pmid: 15068789
references.citation: Nat Rev Drug Discov. 2013 Mar;12(3):205-16
references.pmid: 23411724
references.citation: Mol Biol Cell. 2003 Jul;14(7):3041-54
references.pmid: 12857884
references.citation: Nature. 2011 Jul 04;476(7360):293-7
references.pmid: 21727895
references.citation: Am J Physiol Heart Circ Physiol. 2005 Oct;289(4):H1488-96
references.pmid: 15923313
references.citation: Br J Pharmacol. 2011 Nov;164 Suppl 1:S1-324
references.pmid: 22040146
references.citation: J Biol Chem. 2004 Feb 27;279(9):7840-9
references.pmid: 14681219
references.citation: Biochem Biophys Res Commun. 2008 Feb 15;366(3):717-23
references.pmid: 18078809
references.citation: Gene Ther. 2008 Jan;15(2):126-35
references.pmid: 17989703
references.citation: Mol Endocrinol. 1998 Dec;12(12):1830-45
references.pmid: 9849958
references.citation: Nat Cell Biol. 2009 Mar;11(3):257-68
references.pmid: 19198601
references.citation: J Biol Chem. 1998 Jun 5;273(23):14626-32
references.pmid: 9603980
references.citation: Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11452-7
references.pmid: 21693646
references.citation: J Biol Chem. 2002 Apr 5;277(14):12463-73
references.pmid: 11799111
references.citation: EMBO J. 2012 Jun 13;31(12):2685-96
references.pmid: 22617424
references.citation: Annu Rev Pharmacol Toxicol. 2013;53:127-46
references.pmid: 23020293
references.citation: J Biol Chem. 1998 May 22;273(21):12779-85
references.pmid: 9582304
references.citation: Trends Mol Med. 2011 Mar;17(3):126-39
references.pmid: 21183406
references.citation: Cell. 2001 Dec 28;107(7):843-54
references.pmid: 11779461
references.citation: Science. 2008 Sep 5;321(5894):1350-3
references.pmid: 18772438
references.citation: Nat Rev Cancer. 2002 Apr;2(4):301-10
references.pmid: 12001991
references.citation: Science. 2010 Mar 12;327(5971):1385-9
references.pmid: 20223988
references.citation: J Biol Chem. 2008 May 23;283(21):14469-78
references.pmid: 18378689
references.citation: Mol Endocrinol. 2004 Sep;18(9):2241-54
references.pmid: 15192078
references.citation: EMBO Rep. 2011 Sep 30;12(10):1055-61
references.pmid: 21909076
references.citation: Int J Colorectal Dis. 2010 May;25(5):583-90
references.pmid: 20195621
references.citation: Mol Cell Biol. 2012 Jun;32(11):2054-64
references.pmid: 22473993
references.citation: Genes Dev. 2009 Feb 1;23(3):265-77
references.pmid: 19204114
references.citation: Histochem Cell Biol. 2005 Jul;124(1):35-50
references.pmid: 16028069
references.citation: Gastroenterology. 2010 May;138(5):1681-96
references.pmid: 20417836