Mesd is a universal inhibitor of Wnt coreceptors LRP5 and LRP6 and blocks Wnt/beta-catenin signaling in cancer cells.
Mesd is a specialized chaperone for low-density lipoprotein receptor-related protein 5 (LRP5) and LRP6. In our previous studies, we found that Mesd binds to mature LRP6 on the cell surface and blocks the binding of Wnt antagonist Dickkopf-1 (Dkk1) to LRP6. Herein, we demonstrate that Mesd also binds to LRP5 with a high affinity and is a universal inhibitor of LRP5 and LRP6 ligands. Mesd not only blocks binding of Wnt antagonists Dkk1 and Sclerostin to LRP5 and LRP6 but also inhibits Wnt3A and Rspondin1-induced Wnt/beta-catenin signaling in LRP5- and LRP6-expressing cells. We also found that Mesd, Dkk1, and Sclerostin compete with one another for binding to LRP5 and LRP6 at the cell surface. More importantly, we demonstrated that Mesd is able to suppress LRP6 phosphorylation and Wnt/beta-catenin signaling in prostate cancer PC-3 cells and inhibits PC-3 cell proliferation. Our results indicate that recombinant Mesd protein is a useful tool for studying Wnt/beta-catenin signaling on the cell surface and has a potential therapeutic role in Wnt-dependent cancers.
Lu
Wenyan
W
Department of Biochemistry and Molecular Biology, Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, Alabama 35255-5305, USA.
Liu
Chia-Chen
CC
Thottassery
Jaideep V
JV
Bu
Guojun
G
Li
Yonghe
Y
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D005819:Genetic Markers; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D019485:Bone Morphogenetic Proteins; C501126:DKK1 protein, human; D005819:Genetic Markers; D006131:Growth Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555483:Lrp5 protein, mouse; C555476:Lrp6 protein, mouse; C472170:MESD protein, mouse; D018832:Molecular Chaperones; C422903:SOST protein, human; D051153:Wnt Proteins; D051176:beta Catenin
Cancer Res. 1994 May 15;54(10):2615-21
8168088
Oncogene. 2005 Sep 15;24(41):6323-7
16007200
J Biol Chem. 2005 Jul 22;280(29):26770-5
15908424
Cancer Lett. 2006 Jun 8;237(1):22-32
16023783
Curr Biol. 2001 Jun 26;11(12):951-61
11448771
Cell. 2003 Feb 7;112(3):343-54
12581524
J Biol Chem. 2007 Nov 23;282(47):34420-8
17890782
J Biol Chem. 2004 Apr 23;279(17):17535-42
14739301
FEBS Lett. 2008 Mar 5;582(5):643-50
18242177
N Engl J Med. 2003 Dec 25;349(26):2483-94
14695408
Biochem Biophys Res Commun. 1998 Jul 30;248(3):879-88
9704021
Front Biosci. 2006 Sep 01;11:2093-105
16720296
Dev Cell. 2009 Jul;17(1):9-26
19619488
Int J Oncol. 2004 Sep;25(3):641-9
15289865
J Cell Sci. 2005 Nov 15;118(Pt 22):5305-14
16263759
Pathobiology. 2006;73(5):213-23
17314492
Int Rev Cytol. 2001;209:79-116
11580203
Science. 2001 Aug 31;293(5535):1663-6
11533491
Am J Hum Genet. 2010 May 14;86(5):696-706
20381006
Cancer Res. 2010 Jan 1;70(1):277-87
20048078
Nature. 2000 Sep 28;407(6803):530-5
11029007
Oncogene. 2004 Dec 2;23(56):9129-35
15516984
J Biol Chem. 2005 Jan 28;280(4):2498-502
15545262
Dev Cell. 2004 Oct;7(4):525-34
15469841
J Biol Chem. 2007 May 25;282(21):15903-11
17400545
Cancer Lett. 2005 May 10;222(1):1-10
15837535
Eur J Cancer. 2008 Nov;44(17):2680-8
18790633
J Biol Chem. 2005 May 20;280(20):19883-7
15778503
Cell Signal. 2007 Apr;19(4):659-71
17188462
Eur J Pharmacol. 2009 Jan 5;602(1):8-14
19026633
FEBS Lett. 2006 Oct 2;580(22):5423-8
16989816
Int J Oncol. 2004 Nov;25(5):1337-42
15492823
Cancer Res. 2004 Dec 15;64(24):8860-6
15604245
J Biol Chem. 2009 May 29;284(22):15299-307
19339249
PLoS One. 2009 Jun 05;4(6):e5813
19503830
Bone. 2005 Apr;36(4):585-98
15777744
J Biochem. 1998 Dec 1;124(6):1072-6
9832610
Biochemistry. 2007 Jun 5;46(22):6570-7
17488095
Gene. 1998 Aug 17;216(1):103-11
9714764
Dev Cell. 2005 May;8(5):751-64
15866165
Cancer. 2004 Sep 15;101(6):1345-56
15316903
PLoS One. 2009 Nov 20;4(11):e7930
19936252
Cell. 2003 Feb 7;112(3):355-67
12581525
Nature. 1999 Jul 15;400(6741):276-80
10421371
Trends Genet. 1997 Nov;13(11):421-3
9385834
Science. 2005 Aug 19;309(5738):1256-9
16109882
Mol Biol Cell. 2008 Jun;19(6):2588-96
18400942
J Biol Chem. 2006 May 12;281(19):13247-13257
16543246
Oncogene. 2006 Dec 4;25(57):7469-81
17143291
Oncogene. 2001 Sep 13;20(41):5810-7
11593386
Dev Cell. 2006 Aug;11(2):213-23
16890161
J Cell Biol. 2003 Jul 21;162(2):341-51
12860968
Nat Rev Drug Discov. 2006 Dec;5(12):997-1014
17139285
Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14700-5
17804805
EMBO J. 2004 Mar 24;23(6):1372-80
15014448