DKK and KRM bind LRP5/6

Stable Identifier
R-HSA-3769401
Type
Reaction [binding]
Species
Homo sapiens
Compartment
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DKK1, 2 and 4 are secreted antagonists of WNT signaling that act by binding to LRP5/6 and preventing the formation of an LRP:FZD receptor complex (Semenov et al, 2001; Mao et al, 2001; Bafico et al, 2001; reviewed in Niehrs, 2006). LRP6 has multiple independent WNT binding sites on its surface that are bound by different subsets of WNT proteins (Bourhis et al, 2010; Bourhis et al, 2011). Structural studies show that full length DKK1 binds to an LRP6 site that overlaps with both of these regions, suggesting that WNT and DKK proteins compete for receptor binding (Chen et al, 2011; Ahn et al, 2011; Cheng et al, 2011). Binding of DKK1 is postulated to stabilize LRP6 in an autoinhibited conformation that is relieved upon WNT-binding (Liu et al, 2003; Ahn et al, 2011). In some instances, DKK-mediated inhibition of WNT signaling may be enhanced by the concurrent binding of the single pass transmembrane proteins Kremen1 and 2, although their presence is not absolutely required (Mao et al, 2002; Mao and Niehrs, 2003; Wang et al, 2008). In some cases, DKK2 may also function as a WNT agonist (Brott and Sokol, 2002; Wu et al, 2000; Mao and Nierhs, 2003; Li et al, 2007).

Literature References
PubMed ID Title Journal Year
18502762 Characterization of the Kremen-binding site on Dkk1 and elucidation of the role of Kremen in Dkk-mediated Wnt antagonism

Wang, K, Zhang, Y, Li, X, Chen, L, Wang, H, Wu, J, Zheng, J, Wu, D

J. Biol. Chem. 2008
20093360 Reconstitution of a frizzled8.Wnt3a.LRP6 signaling complex reveals multiple Wnt and Dkk1 binding sites on LRP6

Bourhis, E, Tam, C, Franke, Y, Bazan, JF, Ernst, J, Hwang, J, Costa, M, Cochran, AG, Hannoush, RN

J. Biol. Chem. 2010
12050670 Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling

Mao, B, Wu, W, Davidson, G, Marhold, J, Li, M, Mechler, BM, Delius, H, Hoppe, D, Stannek, P, Walter, C, Glinka, A, Niehrs, C

Nature 2002
11448771 Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6

Semënov, MV, Tamai, K, Brott, BK, Kühl, M, Sokol, S, He, X

Curr Biol 2001
17143291 Function and biological roles of the Dickkopf family of Wnt modulators

Niehrs, C

Oncogene 2006
22000856 Structural basis of Wnt signaling inhibition by Dickkopf binding to LRP5/6

Ahn, VE, Chu, ML, Choi, HJ, Tran, D, Abo, A, Weis, WI

Dev. Cell 2011
11742004 Second cysteine-rich domain of Dickkopf-2 activates canonical Wnt signaling pathway via LRP-6 independently of dishevelled

Li, L, Mao, J, Sun, L, Liu, W, Wu, D

J. Biol. Chem. 2002
12167704 Regulation of Wnt/LRP signaling by distinct domains of Dickkopf proteins

Brott, BK, Sokol, SY

Mol. Cell. Biol. 2002
21984209 Crystal structures of the extracellular domain of LRP6 and its complex with DKK1

Cheng, Z, Biechele, T, Wei, Z, Morrone, S, Moon, RT, Wang, L, Xu, W

Nat. Struct. Mol. Biol. 2011
22000855 Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling

Chen, S, Bubeck, D, MacDonald, BT, Liang, WX, Mao, JH, Malinauskas, T, Llorca, O, Aricescu, AR, Siebold, C, He, X, Jones, EY

Dev. Cell 2011
21944579 Wnt antagonists bind through a short peptide to the first ?-propeller domain of LRP5/6

Bourhis, E, Wang, W, Tam, C, Hwang, J, Zhang, Y, Spittler, D, Huang, OW, Gong, Y, Estevez, A, Zilberleyb, I, Rouge, L, Chiu, C, Wu, Y, Costa, M, Hannoush, RN, Franke, Y, Cochran, AG

Structure 2011
11357136 LDL-receptor-related protein 6 is a receptor for Dickkopf proteins

Mao, B, Wu, W, Li, Y, Hoppe, D, Stannek, P, Glinka, A, Niehrs, C

Nature 2001
12527209 Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling

Mao, B, Niehrs, C

Gene 2003
11137016 Mutual antagonism between dickkopf1 and dickkopf2 regulates Wnt/beta-catenin signalling

Wu, W, Glinka, A, Delius, H, Niehrs, C

Curr. Biol. 2000
12897152 A novel mechanism for Wnt activation of canonical signaling through the LRP6 receptor

Liu, G, Bafico, A, Harris, VK, Aaronson, SA

Mol. Cell. Biol. 2003
11433302 Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow

Bafico, A, Liu, G, Yaniv, A, Gazit, A, Aaronson, SA

Nat. Cell Biol. 2001
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