Reactome | DKK and KRM bind LRP5/6

DKK and KRM bind LRP5/6

Stable Identifier

R-HSA-3769401

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane, extracellular region

ReviewStatus

5/5

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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
20093360	Reconstitution of a frizzled8.Wnt3a.LRP6 signaling complex reveals multiple Wnt and Dkk1 binding sites on LRP6 Franke, Y, Costa, M, Tam, C, Ernst, J, Cochran, AG, Hannoush, RN, Bourhis, E, Hwang, J, Bazan, JF	J. Biol. Chem.	2010
18502762	Characterization of the Kremen-binding site on Dkk1 and elucidation of the role of Kremen in Dkk-mediated Wnt antagonism Wu, J, Zheng, J, Li, X, Chen, L, Wang, K, Wang, H, Zhang, Y, Wu, D	J. Biol. Chem.	2008
12050670	Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling Mechler, BM, Wu, W, Li, M, Marhold, J, Niehrs, C, Stannek, P, Mao, B, Delius, H, Walter, C, Hoppe, D, Davidson, G, Glinka, A	Nature	2002
11448771	Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6 Tamai, K, Brott, BK, Semënov, MV, Kühl, M, He, X, Sokol, S	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 Weis, WI, Abo, A, Tran, D, Ahn, VE, Choi, HJ, Chu, ML	Dev. Cell	2011
11742004	Second cysteine-rich domain of Dickkopf-2 activates canonical Wnt signaling pathway via LRP-6 independently of dishevelled Li, L, Liu, W, Mao, J, Sun, L, 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 Xu, W, Cheng, Z, Wang, L, Wei, Z, Moon, RT, Biechele, T, Morrone, S	Nat. Struct. Mol. Biol.	2011
22000855	Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling Chen, S, He, X, MacDonald, BT, Mao, JH, Bubeck, D, Aricescu, AR, Malinauskas, T, Llorca, O, Jones, EY, Liang, WX, Siebold, C	Dev. Cell	2011
21944579	Wnt antagonists bind through a short peptide to the first ?-propeller domain of LRP5/6 Estevez, A, Franke, Y, Cochran, AG, Gong, Y, Spittler, D, Bourhis, E, Wu, Y, Zhang, Y, Wang, W, Rouge, L, Costa, M, Tam, C, Hannoush, RN, Zilberleyb, I, Hwang, J, Huang, OW, Chiu, C	Structure	2011
11357136	LDL-receptor-related protein 6 is a receptor for Dickkopf proteins Wu, W, Niehrs, C, Stannek, P, Mao, B, Li, Y, Hoppe, D, Glinka, A	Nature	2001
12527209	Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling Niehrs, C, Mao, B	Gene	2003
11137016	Mutual antagonism between dickkopf1 and dickkopf2 regulates Wnt/beta-catenin signalling Wu, W, Niehrs, C, Delius, H, Glinka, A	Curr. Biol.	2000
12897152	A novel mechanism for Wnt activation of canonical signaling through the LRP6 receptor Harris, VK, Aaronson, SA, Bafico, A, Liu, G	Mol. Cell. Biol.	2003
11433302	Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow Yaniv, A, Gazit, A, Aaronson, SA, Bafico, A, Liu, G	Nat. Cell Biol.	2001