Regulation of the Low-Density Lipoprotein Receptor-Related Protein LRP6 and Its Association With Disease: Wnt/β-Catenin Signaling and Beyond

Wonyoung Jeong, Eek-Hoon Jho, Wonyoung Jeong, Eek-Hoon Jho

Abstract

Wnt signaling plays crucial roles in development and tissue homeostasis, and its dysregulation leads to various diseases, notably cancer. Wnt/β-catenin signaling is initiated when the glycoprotein Wnt binds to and forms a ternary complex with the Frizzled and low-density lipoprotein receptor-related protein 5/6 (LRP5/6). Despite being identified as a Wnt co-receptor over 20 years ago, the molecular mechanisms governing how LRP6 senses Wnt and transduces downstream signaling cascades are still being deciphered. Due to its role as one of the main Wnt signaling components, the dysregulation or mutation of LRP6 is implicated in several diseases such as cancer, neurodegeneration, metabolic syndrome and skeletal disease. Herein, we will review how LRP6 is activated by Wnt stimulation and explore the various regulatory mechanisms involved. The participation of LRP6 in other signaling pathways will also be discussed. Finally, the relationship between LRP6 dysregulation and disease will be examined in detail.

Keywords: LRP6; Wnt; cancer; metabolism; signaling.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Jeong and Jho.

Figures

FIGURE 1
FIGURE 1
Core activation mechanisms of LRP6 via Wnt stimulation. (A) In the absence of Wnt, the scaffold protein Axin together with APC, GSK3, and CK1 form the β-catenin destruction complex. β-catenin interacts with the complex and is phosphorylated by GSK3 and CK1α (CK1). Phosphorylated β-catenin is ubiquitinated by SCFβ–Trcp and degraded by the proteasome. Protein levels of β-catenin thus remain low, and β-catenin-dependent transcription of Wnt/β-catenin target genes is suppressed. (B) Wnt interacts with the FZD and LRP6 receptors. Axin-bound GSK3 and CK1γ phosphorylate PPPS/TP motifs in the intracellular domain of LRP6. Phosphorylated LRP6 serves as a docking site for Axin, facilitating the interaction between Axin and LRP6 and inhibiting the kinase activity of GSK3. This causes the dissociation and inactivation of the β-catenin destruction complex, leading to β-catenin stabilization and activation of Wnt/β-catenin target gene transcription. (C) Treatment of Wnt induces LRP6 aggregates in a DVL-dependent manner. In this condition, FZDs, Axin, and GSK3 can also aggregate with LRP6, generating LRP6 signalosomes. PIP2 is generated via DVL-bound PIP5K1. PIP2 accelerates the formation of LRP6 signalosomes and phosphorylation of LRP6, resulting in further activation of Wnt/β-catenin signaling.
FIGURE 2
FIGURE 2
Regulation of LRP6 phosphorylation. Phosphorylation of LRP6 can be regulated by various proteins through distinct mechanisms. PTH interacts with the extracellular domain of LRP6 and facilitates its phosphorylation. In contrast, Wnt5a and PEDF interact with the extracellular domain of LRP6 and inhibit LRP6 phosphorylation. GRK5/6, MAPKs, and RTKs facilitate phosphorylation of LRP6 in the cytoplasm, and Lypd6 facilitates phosphorylation of LRP6 in the plasma membrane. Src and Fer and Merlin inhibit phosphorylation of LRP6 in the cytoplasm. Gβ1γ2 and TMEM198 promote phosphorylation of LRP6 in GSK3 and CK1-dependent manners, respectively. Arf1/6 facilitates the phosphorylation of LRP6 in a PIP2-dependent manner.
FIGURE 3
FIGURE 3
Regulation of LRP6 internalization. (A) Interaction between LRP6, DKKs, and Kremen1/2 promotes clathrin-mediated internalization, resulting in degradation or inhibition of LRP6. ANGPTL4, Bighead, and fucosylation of LRP6 promotes internalization of LRP6 at the extracellular level, thereby inhibiting LRP6 function and Wnt/β-catenin signaling. Dab2 and AAK function at the intracellular level and promote clathrin-mediated internalization of LRP6, resulting in Wnt/β-catenin signaling suppression. On the other hand, EpCAM inhibits LRP6-DKK-Kremen1/2 complex formation, resulting in Wnt signaling activation. (B) Interaction among LRP6, FZDs, and Wnt promotes caveolin-mediated internalization, resulting in LRP6 activation and MVB formation. RAB8B, FinA, and TFG promote Wnt3a-mediated internalization of LRP6 and Wnt/β-catenin signaling at the intracellular level. However, Waif1 compromises Wnt-LRP6 interaction and inhibits Wnt/β-catenin signaling. APC inhibits Clathrin and AP2-mediated internalization of LRP6 at the intracellular level, resulting in suppression of Wnt/β-catenin signaling.
FIGURE 4
FIGURE 4
Regulation of LRP6 maturation and stability. The transmembrane protein LRP6 undergoes several folding and maturation processes to translocate to the plasma membrane and properly function as a Wnt co-receptor. Mesd, USP19, GRP94, and GPR37 promote proper folding of LRP6. Glycosylation and palmitoylation of LRP6 are essential for its maturation. Mest/Peg1 inhibits glycosylation of LRP6 and immature LRP6 is mono-ubiquitinated, resulting in ER retention. Folded and mature LRP6 localizes to the plasma membrane, and CD44 promotes membrane localization of LRP6. ZNRF3 and DVL downregulate LRP6 protein levels, and USP6 and R-spondins antagonize ZNRF3 function. Extracellular stimuli such as hypoxia, ER stress, and starvation also degrade LRP6.
FIGURE 5
FIGURE 5
Role of LRP6 as a regulator of other signaling. (A) LRP6 as a regulator of GPCR signaling. In the basal state, LRP6 interacts with G protein Gαs. In the presence of the GPCR ligand PTH, a LRP6-PTH-PTH1R ternary complex is formed, which promotes aggregation of LRP6 and membrane localization of Gαs. Production of cAMP is also upregulated in a Gαs-AC-dependent manner. cAMP activates PKA, which promotes phosphorylation of LRP6 and CREB, two well-known downstream targets of PKA. (B) LRP6 as a regulator of non-canonical Wnt signaling. Wnt5a interacts with ROR1/2 and FZD, resulting in activation of Rac, a non-canonical Wnt signaling target. Wnt5a can also interact with LRP6. In these conditions, the binding affinity of ROR1/2 and FZD to Wnt5a is reduced. As a result, Rac becomes inactive and non-canonical Wnt signaling is inhibited. Because LRP6-Wnt5a binding weakens LRP6-Wnt3a interaction, Wnt/β-catenin signaling is also inhibited. (C) LRP6 as a regulator of Hippo signaling. In a nutrient rich state, LRP6 is O-GlcNAcylated and interacts with Merlin. In this condition, activity of LATS1/2 is maintained at low levels, resulting in stabilization and activation of YAP. In nutrient starvation conditions, O-GlcNAcylation and protein levels of LRP6 are both downregulated, and Merlin changes its binding partner from LRP6 to LATS1/2, resulting in activation of LATS1/2. YAP is phosphorylated by LATS1/2 and becomes inactive. (D) LRP6 as a regulator of Wnt/STOP signaling. In G1/S phase, cyclin Y protein levels are less abundant and the phosphorylation state of LRP6 is low, resulting in higher GSK3 activity. GSK3-target proteins are thus phosphorylated and targeted for proteasomal degradation. In G2/M phase, cyclin Y protein levels peak and promote LRP6 phosphorylation, resulting in inactivation of GSK3 and stabilization of GSK3-target proteins.

References

    1. Abe T., Zhou P., Jackman K., Capone C., Casolla B., Hochrainer K., et al. (2013). Lipoprotein receptor-related protein-6 protects the brain from ischemic injury. Stroke 44 2284–2291. 10.1161/strokeaha.113.001320
    1. Aberle H., Bauer A., Stappert J., Kispert A., Kemler R. (1997). Beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 16 3797–3804. 10.1093/emboj/16.13.3797
    1. Abrami L., Kunz B., Iacovache I., van der Goot F. G. (2008). Palmitoylation and ubiquitination regulate exit of the Wnt signaling protein LRP6 from the endoplasmic reticulum. Proc. Natl. Acad. Sci. U.S.A. 105 5384–5389. 10.1073/pnas.0710389105
    1. Acebron S. P., Niehrs C. (2016). β-catenin-independent roles of Wnt/LRP6 signaling. Trends Cell Biol. 26 956–967. 10.1016/j.tcb.2016.07.009
    1. Acebron S. P., Karaulanov E., Berger B. S., Huang Y. L., Niehrs C. (2014). Mitotic wnt signaling promotes protein stabilization and regulates cell size. Mol. Cell 54 663–674. 10.1016/j.molcel.2014.04.014
    1. Agajanian M. J., Walker M. P., Axtman A. D., Ruela-de-Sousa R. R., Serafin D. S., Rabinowitz A. D., et al. (2019). WNT activates the AAK1 kinase to promote clathrin-mediated endocytosis of LRP6 and establish a negative feedback loop. Cell Rep. 26 79–93.e8. 10.1016/j.celrep.2018.12.023
    1. Alarcón M. A., Medina M. A., Hu Q., Avila M. E., Bustos B. I., Pérez-Palma E., et al. (2013). A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer’s disease. Neurobiol. Aging 34 e1709–e1718. 10.1016/j.neurobiolaging.2012.11.004
    1. Avila M. E., Sepúlveda F. J., Burgos C. F., Moraga-Cid G., Parodi J., Moon R. T., et al. (2010). Canonical Wnt3a modulates intracellular calcium and enhances excitatory neurotransmission in hippocampal neurons. J. Biol. Chem. 285 18939–18947. 10.1074/jbc.M110.103028
    1. Azzolin L., Panciera T., Soligo S., Enzo E., Bicciato S., Dupont S., et al. (2014). YAP/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response. Cell 158 157–170. 10.1016/j.cell.2014.06.013
    1. Babij P., Zhao W., Small C., Kharode Y., Yaworsky P. J., Bouxsein M. L., et al. (2003). High bone mass in mice expressing a mutant LRP5 gene. J. Bone Miner. Res. 18 960–974. 10.1359/jbmr.2003.18.6.960
    1. Bafico A., Liu G., Yaniv A., Gazit A., Aaronson S. A. (2001). Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat. Cell Biol. 3 683–686. 10.1038/35083081
    1. Balemans W., Ebeling M., Patel N., Van Hul E., Olson P., Dioszegi M., et al. (2001). Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum. Mol. Genet. 10 537–543. 10.1093/hmg/10.5.537
    1. Berendsen A. D., Fisher L. W., Kilts T. M., Owens R. T., Robey P. G., Gutkind J. S., et al. (2011). Modulation of canonical Wnt signaling by the extracellular matrix component biglycan. Proc. Natl. Acad. Sci. U.S.A. 108 17022–17027. 10.1073/pnas.1110629108
    1. Berger B. S., Acebron S. P., Herbst J., Koch S., Niehrs C. (2017). Parkinson’s disease-associated receptor GPR37 is an ER chaperone for LRP6. EMBO Rep. 18 712–725. 10.15252/embr.201643585
    1. Berwick D. C., Harvey K. (2012). LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6. Hum. Mol. Genet. 21 4966–4979. 10.1093/hmg/dds342
    1. Bilic J., Huang Y. L., Davidson G., Zimmermann T., Cruciat C. M., Bienz M., et al. (2007). Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science 316 1619–1622. 10.1126/science.1137065
    1. Bryja V., Andersson E. R., Schambony A., Esner M., Bryjová L., Biris K. K., et al. (2009). The extracellular domain of Lrp5/6 inhibits noncanonical Wnt signaling in vivo. Mol. Biol. Cell 20 924–936. 10.1091/mbc.e08-07-0711
    1. Bugter J. M., Fenderico N., Maurice M. M. (2021). Mutations and mechanisms of WNT pathway tumour suppressors in cancer. Nat. Rev. Cancer 21 5–21. 10.1038/s41568-020-00307-z
    1. Carmon K. S., Gong X., Lin Q., Thomas A., Liu Q. (2011). R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Proc. Natl. Acad. Sci. U.S.A. 108 11452–11457. 10.1073/pnas.1106083108
    1. Červenka I., Wolf J., Mašek J., Krejci P., Wilcox W. R., Kozubík A., et al. (2011). Mitogen-activated protein kinases promote WNT/beta-catenin signaling via phosphorylation of LRP6. Mol. Cell. Biol. 31 179–189. 10.1128/mcb.00550-10
    1. Chen J., Rajasekaran M., Xia H., Kong S. N., Deivasigamani A., Sekar K., et al. (2018). CDK1-mediated BCL9 phosphorylation inhibits clathrin to promote mitotic Wnt signalling. EMBO J. 37:e99395. 10.15252/embj.201899395
    1. Chen M., Philipp M., Wang J., Premont R. T., Garrison T. R., Caron M. G., et al. (2009). G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway. J. Biol. Chem. 284 35040–35048. 10.1074/jbc.M109.047456
    1. Chen Q., Su Y., Wesslowski J., Hagemann A. I., Ramialison M., Wittbrodt J., et al. (2014). Tyrosine phosphorylation of LRP6 by Src and Fer inhibits Wnt/β-catenin signalling. EMBO Rep. 15 1254–1267. 10.15252/embr.201439644
    1. Cheng Z., Biechele T., Wei Z., Morrone S., Moon R. T., Wang L., et al. (2011). Crystal structures of the extracellular domain of LRP6 and its complex with DKK1. Nat. Struct. Mol. Biol. 18 1204–1210. 10.1038/nsmb.2139
    1. Colozza G., Jami-Alahmadi Y., Dsouza A., Tejeda-Muñoz N., Albrecht L. V., Sosa E. A., et al. (2020). Wnt-inducible Lrp6-APEX2 interacting proteins identify ESCRT machinery and Trk-fused gene as components of the Wnt signaling pathway. Sci. Rep. 10:21555. 10.1038/s41598-020-78019-5
    1. Cselenyi C. S., Jernigan K. K., Tahinci E., Thorne C. A., Lee L. A., Lee E. (2008). LRP6 transduces a canonical Wnt signal independently of Axin degradation by inhibiting GSK3’s phosphorylation of beta-catenin. Proc. Natl. Acad. Sci. U.S.A. 105 8032–8037. 10.1073/pnas.0803025105
    1. Davidson G., Shen J., Huang Y. L., Su Y., Karaulanov E., Bartscherer K., et al. (2009). Cell cycle control of wnt receptor activation. Dev. Cell 17 788–799. 10.1016/j.devcel.2009.11.006
    1. Davidson G., Wu W., Shen J., Bilic J., Fenger U., Stannek P., et al. (2005). Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction. Nature 438 867–872. 10.1038/nature04170
    1. De Ferrari G. V., Papassotiropoulos A., Biechele T., Wavrant De-Vrieze F., Avila M. E., Major M. B., et al. (2007). Common genetic variation within the low-density lipoprotein receptor-related protein 6 and late-onset Alzheimer’s disease. Proc. Natl. Acad. Sci. U.S.A. 104 9434–9439. 10.1073/pnas.0603523104
    1. Demir K., Kirsch N., Beretta C. A., Erdmann G., Ingelfinger D., Moro E., et al. (2013). RAB8B is required for activity and caveolar endocytosis of LRP6. Cell Rep. 4 1224–1234. 10.1016/j.celrep.2013.08.008
    1. Ding Y., Colozza G., Sosa E. A., Moriyama Y., Rundle S., Salwinski L., et al. (2018). Bighead is a Wnt antagonist secreted by the Xenopus Spemann organizer that promotes Lrp6 endocytosis. Proc. Natl. Acad. Sci. U.S.A. 115 E9135–E9144. 10.1073/pnas.1812117115
    1. Dong Y., Zhang Y., Kang W., Wang G., Chen H., Higashimori A., et al. (2019). VSTM2A suppresses colorectal cancer and antagonizes Wnt signaling receptor LRP6. Theranostics 9 6517–6531. 10.7150/thno.34989
    1. Elliott C., Rojo A. I., Ribe E., Broadstock M., Xia W., Morin P., et al. (2018). A role for APP in Wnt signalling links synapse loss with β-amyloid production. Transl. Psychiatry 8:179. 10.1038/s41398-018-0231-6
    1. Ettenberg S. A., Charlat O., Daley M. P., Liu S., Vincent K. J., Stuart D. D., et al. (2010). Inhibition of tumorigenesis driven by different Wnt proteins requires blockade of distinct ligand-binding regions by LRP6 antibodies. Proc. Natl. Acad. Sci. U.S.A. 107 15473–15478. 10.1073/pnas.1007428107
    1. Ferrari N., Ranftl R., Chicherova I., Slaven N. D., Moeendarbary E., Farrugia A. J., et al. (2019). Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts. Nat. Commun. 10:130. 10.1038/s41467-018-07987-0
    1. Gan L., Cookson M. R., Petrucelli L., La Spada A. R. (2018). Converging pathways in neurodegeneration, from genetics to mechanisms. Nat. Neurosci. 21 1300–1309. 10.1038/s41593-018-0237-7
    1. Go G. W., Srivastava R., Hernandez-Ono A., Gang G., Smith S. B., Booth C. J., et al. (2014). The combined hyperlipidemia caused by impaired Wnt-LRP6 signaling is reversed by Wnt3a rescue. Cell Metab. 19 209–220. 10.1016/j.cmet.2013.11.023
    1. Gong Y., Slee R. B., Fukai N., Rawadi G., Roman-Roman S., Reginato A. M., et al. (2001). LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107 513–523. 10.1016/s0092-8674(01)00571-2
    1. Greten F. R., Grivennikov S. I. (2019). Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 51 27–41. 10.1016/j.immuni.2019.06.025
    1. Grumolato L., Liu G., Mong P., Mudbhary R., Biswas R., Arroyave R., et al. (2010). Canonical and noncanonical Wnts use a common mechanism to activate completely unrelated coreceptors. Genes Dev. 24 2517–2530. 10.1101/gad.1957710
    1. Hao H. X., Xie Y., Zhang Y., Charlat O., Oster E., Avello M., et al. (2012). ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 485 195–200. 10.1038/nature11019
    1. Holmen S. L., Giambernardi T. A., Zylstra C. R., Buckner-Berghuis B. D., Resau J. H., Hess J. F., et al. (2004). Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6. J. Bone Miner. Res. 19 2033–2040. 10.1359/jbmr.040907
    1. Hong S., Feng L., Yang Y., Jiang H., Hou X., Guo P., et al. (2020). In situ fucosylation of the Wnt co-receptor LRP6 increases its endocytosis and reduces Wnt/β-catenin signaling. Cell Chem. Biol. 27 1140–1150.e4. 10.1016/j.chembiol.2020.06.015
    1. Hong Y., Manoharan I., Suryawanshi A., Shanmugam A., Swafford D., Ahmad S., et al. (2016). Deletion of LRP5 and LRP6 in dendritic cells enhances antitumor immunity. Oncoimmunology 5:e1115941. 10.1080/2162402x.2015.1115941
    1. Hsieh J. C., Lee L., Zhang L., Wefer S., Brown K., DeRossi C., et al. (2003). Mesd encodes an LRP5/6 chaperone essential for specification of mouse embryonic polarity. Cell 112 355–367. 10.1016/s0092-8674(03)00045-x
    1. Jeong W., Kim S., Lee U., Zhong Z. A., Savitsky M., Kwon H., et al. (2020). LDL receptor-related protein LRP6 senses nutrient levels and regulates Hippo signaling. EMBO Rep. 21:e50103. 10.15252/embr.202050103
    1. Jernigan K. K., Cselenyi C. S., Thorne C. A., Hanson A. J., Tahinci E., Hajicek N., et al. (2010). Gbetagamma activates GSK3 to promote LRP6-mediated beta-catenin transcriptional activity. Sci. Signal. 3:ra37. 10.1126/scisignal.2000647
    1. Jia Q., Bu Y., Wang Z., Chen B., Zhang Q., Yu S., et al. (2017). Maintenance of stemness is associated with the interation of LRP6 and heparin-binding protein CCN2 autocrined by hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 36:117. 10.1186/s13046-017-0576-3
    1. Jiang X., Charlat O., Zamponi R., Yang Y., Cong F. (2015). Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases. Mol. Cell 58 522–533. 10.1016/j.molcel.2015.03.015
    1. Jiang Y., He X., Howe P. H. (2012). Disabled-2 (Dab2) inhibits Wnt/β-catenin signalling by binding LRP6 and promoting its internalization through clathrin. EMBO J. 31 2336–2349. 10.1038/emboj.2012.83
    1. Joeng K. S., Schumacher C. A., Zylstra-Diegel C. R., Long F., Williams B. O. (2011). Lrp5 and Lrp6 redundantly control skeletal development in the mouse embryo. Dev. Biol. 359 222–229. 10.1016/j.ydbio.2011.08.020
    1. Joiner D. M., Ke J., Zhong Z., Xu H. E., Williams B. O. (2013). LRP5 and LRP6 in development and disease. Trends Endocrinol. Metab. 24 31–39. 10.1016/j.tem.2012.10.003
    1. Jung H., Lee S. K., Jho E. H. (2011). Mest/Peg1 inhibits Wnt signalling through regulation of LRP6 glycosylation. Biochem. J. 436 263–269. 10.1042/bj20101512
    1. Kagermeier-Schenk B., Wehner D., Ozhan-Kizil G., Yamamoto H., Li J., Kirchner K., et al. (2011). Waif1/5T4 inhibits Wnt/β-catenin signaling and activates noncanonical Wnt pathways by modifying LRP6 subcellular localization. Dev. Cell 21 1129–1143. 10.1016/j.devcel.2011.10.015
    1. Keramati A. R., Singh R., Lin A., Faramarzi S., Ye Z. J., Mane S., et al. (2011). Wild-type LRP6 inhibits, whereas atherosclerosis-linked LRP6R611C increases PDGF-dependent vascular smooth muscle cell proliferation. Proc. Natl. Acad. Sci. U.S.A. 108 1914–1918. 10.1073/pnas.1019443108
    1. Khan Z., Vijayakumar S., de la Torre T. V., Rotolo S., Bafico A. (2007). Analysis of endogenous LRP6 function reveals a novel feedback mechanism by which Wnt negatively regulates its receptor. Mol. Cell. Biol. 27 7291–7301. 10.1128/mcb.00773-07
    1. Kikuchi A., Yamamoto H., Sato A. (2009). Selective activation mechanisms of Wnt signaling pathways. Trends Cell Biol. 19 119–129. 10.1016/j.tcb.2009.01.003
    1. Kim I., Pan W., Jones S. A., Zhang Y., Zhuang X., Wu D. (2013). Clathrin and AP2 are required for PtdIns(4,5)P2-mediated formation of LRP6 signalosomes. J. Cell Biol. 200 419–428. 10.1083/jcb.201206096
    1. Kim M., Kim S., Lee S. H., Kim W., Sohn M. J., Kim H. S., et al. (2016). Merlin inhibits Wnt/β-catenin signaling by blocking LRP6 phosphorylation. Cell Death Differ. 23 1638–1647. 10.1038/cdd.2016.54
    1. Kim W., Kim S. Y., Kim T., Kim M., Bae D. J., Choi H. I., et al. (2013). ADP-ribosylation factors 1 and 6 regulate Wnt/β-catenin signaling via control of LRP6 phosphorylation. Oncogene 32 3390–3396. 10.1038/onc.2012.373
    1. Kirsch N., Chang L. S., Koch S., Glinka A., Dolde C., Colozza G., et al. (2017). Angiopoietin-like 4 Is a Wnt Signaling Antagonist that Promotes LRP6 Turnover. Dev. Cell 43 71.e–82.e. 10.1016/j.devcel.2017.09.011
    1. Kitagawa M., Hatakeyama S., Shirane M., Matsumoto M., Ishida N., Hattori K., et al. (1999). An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin. EMBO J. 18 2401–2410. 10.1093/emboj/18.9.2401
    1. Koo B. K., Spit M., Jordens I., Low T. Y., Stange D. E., van de Wetering M., et al. (2012). Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 488 665–669. 10.1038/nature11308
    1. Koslowski M. J., Teltschik Z., Beisner J., Schaeffeler E., Wang G., Kübler I., et al. (2012). Association of a functional variant in the Wnt co-receptor LRP6 with early onset ileal Crohn’s disease. PLoS Genet. 8:e1002523. 10.1371/journal.pgen.1002523
    1. Krejci P., Aklian A., Kaucka M., Sevcikova E., Prochazkova J., Masek J. K., et al. (2012). Receptor tyrosine kinases activate canonical WNT/β-catenin signaling via MAP kinase/LRP6 pathway and direct β-catenin phosphorylation. PLoS One 7:e35826. 10.1371/journal.pone.0035826
    1. Kumari U., Tan E. K. (2009). LRRK2 in Parkinson’s disease: genetic and clinical studies from patients. FEBS J. 276 6455–6463. 10.1111/j.1742-4658.2009.07344.x
    1. Lai K. K. Y., Kweon S. M., Chi F., Hwang E., Kabe Y., Higashiyama R., et al. (2017). Stearoyl-CoA desaturase promotes liver fibrosis and tumor development in mice via a Wnt positive-signaling loop by stabilization of low-density lipoprotein-receptor-related proteins 5 and 6. Gastroenterology 152 1477–1491. 10.1053/j.gastro.2017.01.021
    1. Landskroner-Eiger S., Qiu C., Perrotta P., Siragusa M., Lee M. Y., Ulrich V., et al. (2015). Endothelial miR-17∼92 cluster negatively regulates arteriogenesis via miRNA-19 repression of WNT signaling. Proc. Natl. Acad. Sci. U.S.A. 112 12812–12817. 10.1073/pnas.1507094112
    1. Lemieux E., Cagnol S., Beaudry K., Carrier J., Rivard N. (2015). Oncogenic KRAS signalling promotes the Wnt/β-catenin pathway through LRP6 in colorectal cancer. Oncogene 34 4914–4927. 10.1038/onc.2014.416
    1. Li C., Wang W., Xie L., Luo X., Cao X., Wan M. (2016). Lipoprotein receptor-related protein 6 is required for parathyroid hormone-induced Sost suppression. Ann. N. Y. Acad. Sci. 1364 62–73. 10.1111/nyas.12750
    1. Li C., Xing Q., Yu B., Xie H., Wang W., Shi C., et al. (2013). Disruption of LRP6 in osteoblasts blunts the bone anabolic activity of PTH. J. Bone Miner. Res. 28 2094–2108. 10.1002/jbmr.1962
    1. Li X., Zhang Y., Kang H., Liu W., Liu P., Zhang J., et al. (2005). Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem. 280 19883–19887. 10.1074/jbc.M413274200
    1. Li Y., Lu W., He X., Schwartz A. L., Bu G. (2004). LRP6 expression promotes cancer cell proliferation and tumorigenesis by altering beta-catenin subcellular distribution. Oncogene 23 9129–9135. 10.1038/sj.onc.1208123
    1. Lian G., Dettenhofer M., Lu J., Downing M., Chenn A., Wong T., et al. (2016). Filamin A- and formin 2-dependent endocytosis regulates proliferation via the canonical Wnt pathway. Development 143 4509–4520. 10.1242/dev.139295
    1. Liang J., Fu Y., Cruciat C. M., Jia S., Wang Y., Tong Z., et al. (2011). Transmembrane protein 198 promotes LRP6 phosphorylation and Wnt signaling activation. Mol. Cell. Biol. 31 2577–2590. 10.1128/mcb.05103-11
    1. Lin Y., Jian Z., Jin H., Wei X., Zou X., Guan R., et al. (2020). Long non-coding RNA DLGAP1-AS1 facilitates tumorigenesis and epithelial-mesenchymal transition in hepatocellular carcinoma via the feedback loop of miR-26a/b-5p/IL-6/JAK2/STAT3 and Wnt/β-catenin pathway. Cell Death Dis. 11:34. 10.1038/s41419-019-2188-7
    1. Lindvall C., Zylstra C. R., Evans N., West R. A., Dykema K., Furge K. A., et al. (2009). The Wnt co-receptor Lrp6 is required for normal mouse mammary gland development. PLoS One 4:e5813. 10.1371/journal.pone.0005813
    1. Liu B., Staron M., Hong F., Wu B. X., Sun S., Morales C., et al. (2013). Essential roles of grp94 in gut homeostasis via chaperoning canonical Wnt pathway. Proc. Natl. Acad. Sci. U.S.A. 110 6877–6882. 10.1073/pnas.1302933110
    1. Liu C. C., Prior J., Piwnica-Worms D., Bu G. (2010). LRP6 overexpression defines a class of breast cancer subtype and is a target for therapy. Proc. Natl. Acad. Sci. U.S.A. 107 5136–5141. 10.1073/pnas.0911220107
    1. Liu C. C., Tsai C. W., Deak F., Rogers J., Penuliar M., Sung Y. M., et al. (2014). Deficiency in LRP6-mediated Wnt signaling contributes to synaptic abnormalities and amyloid pathology in Alzheimer’s disease. Neuron 84 63–77. 10.1016/j.neuron.2014.08.048
    1. Liu C., Li Y., Semenov M., Han C., Baeg G. H., Tan Y., et al. (2002). Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108 837–847. 10.1016/s0092-8674(02)00685-2
    1. Liu G., Bafico A., Harris V. K., Aaronson S. A. (2003). A novel mechanism for Wnt activation of canonical signaling through the LRP6 receptor. Mol. Cell. Biol. 23 5825–5835. 10.1128/mcb.23.16.5825-5835.2003
    1. Liu W., Mani S., Davis N. R., Sarrafzadegan N., Kavathas P. B., Mani A. (2008). Mutation in EGFP domain of LDL receptor-related protein 6 impairs cellular LDL clearance. Circ. Res. 103 1280–1288. 10.1161/circresaha.108.183863
    1. Liu W., Xing F., Iiizumi-Gairani M., Okuda H., Watabe M., Pai S. K., et al. (2012). N-myc downstream regulated gene 1 modulates Wnt-β-catenin signalling and pleiotropically suppresses metastasis. EMBO Mol. Med. 4 93–108. 10.1002/emmm.201100190
    1. Lu H., Ma J., Yang Y., Shi W., Luo L. (2013). EpCAM is an endoderm-specific Wnt derepressor that licenses hepatic development. Dev. Cell 24 543–553. 10.1016/j.devcel.2013.01.021
    1. MacDonald B. T., He X. (2012). Frizzled and LRP5/6 receptors for Wnt/β-catenin signaling. Cold Spring Harb. Perspect. Biol. 4:a007880. 10.1101/cshperspect.a007880
    1. MacDonald B. T., Tamai K., He X. (2009). Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17 9–26. 10.1016/j.devcel.2009.06.016
    1. Madan B., Walker M. P., Young R., Quick L., Orgel K. A., Ryan M., et al. (2016). USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds. Proc. Natl. Acad. Sci. U.S.A. 113 E2945–E2954. 10.1073/pnas.1605691113
    1. Mani A., Radhakrishnan J., Wang H., Mani A., Mani M. A., Nelson-Williams C., et al. (2007). LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315 1278–1282. 10.1126/science.1136370
    1. Mao B., Wu W., Davidson G., Marhold J., Li M., Mechler B. M., et al. (2002). Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature 417 664–667. 10.1038/nature756
    1. Mao B., Wu W., Li Y., Hoppe D., Stannek P., Glinka A., et al. (2001). LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature 411 321–325. 10.1038/35077108
    1. Mao J., Wang J., Liu B., Pan W., Farr G. H., III, Flynn C., et al. (2001). Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol. Cell 7 801–809. 10.1016/s1097-2765(01)00224-6
    1. Meng Z., Moroishi T., Guan K. L. (2016). Mechanisms of Hippo pathway regulation. Genes Dev. 30 1–17. 10.1101/gad.274027.115
    1. Metcalfe C., Mendoza-Topaz C., Mieszczanek J., Bienz M. (2010). Stability elements in the LRP6 cytoplasmic tail confer efficient signalling upon DIX-dependent polymerization. J. Cell Sci. 123(Pt 9) 1588–1599. 10.1242/jcs.067546
    1. Nava P., Koch S., Laukoetter M. G., Lee W. Y., Kolegraff K., Capaldo C. T., et al. (2010). Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways. Immunity 32 392–402. 10.1016/j.immuni.2010.03.001
    1. Nusse R., Clevers H. (2017). Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 169 985–999. 10.1016/j.cell.2017.05.016
    1. Özhan G., Sezgin E., Wehner D., Pfister A. S., Kühl S. J., Kagermeier-Schenk B., et al. (2013). Lypd6 enhances Wnt/β-catenin signaling by promoting Lrp6 phosphorylation in raft plasma membrane domains. Dev. Cell 26 331–345. 10.1016/j.devcel.2013.07.020
    1. Pan D. (2010). The hippo signaling pathway in development and cancer. Dev. Cell 19 491–505. 10.1016/j.devcel.2010.09.011
    1. Pan W., Choi S. C., Wang H., Qin Y., Volpicelli-Daley L., Swan L., et al. (2008). Wnt3a-mediated formation of phosphatidylinositol 4,5-bisphosphate regulates LRP6 phosphorylation. Science 321 1350–1353. 10.1126/science.1160741
    1. Park K., Lee K., Zhang B., Zhou T., He X., Gao G., et al. (2011). Identification of a novel inhibitor of the canonical Wnt pathway. Mol. Cell. Biol. 31 3038–3051. 10.1128/mcb.01211-10
    1. Perrody E., Abrami L., Feldman M., Kunz B., Urbé S., van der Goot F. G. (2016). Ubiquitin-dependent folding of the Wnt signaling coreceptor LRP6. Elife 5:e19083. 10.7554/eLife.19083
    1. Pinson K. I., Brennan J., Monkley S., Avery B. J., Skarnes W. C. (2000). An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407 535–538. 10.1038/35035124
    1. Raines E. W. (2004). PDGF and cardiovascular disease. Cytokine Growth Factor Rev. 15 237–254. 10.1016/j.cytogfr.2004.03.004
    1. Regard J. B., Zhong Z., Williams B. O., Yang Y. (2012). Wnt signaling in bone development and disease: making stronger bone with Wnts. Cold Spring Harb. Perspect. Biol. 4:a007997. 10.1101/cshperspect.a007997
    1. Ren D. N., Chen J., Li Z., Yan H., Yin Y., Wo D., et al. (2015). LRP5/6 directly bind to Frizzled and prevent Frizzled-regulated tumour metastasis. Nat. Commun. 6:6906. 10.1038/ncomms7906
    1. Rochlani Y., Pothineni N. V., Kovelamudi S., Mehta J. L. (2017). Metabolic syndrome: pathophysiology, management, and modulation by natural compounds. Ther. Adv. Cardiovasc. Dis. 11 215–225. 10.1177/1753944717711379
    1. Saito-Diaz K., Benchabane H., Tiwari A., Tian A., Li B., Thompson J. J., et al. (2018). APC inhibits ligand-independent Wnt signaling by the clathrin endocytic pathway. Dev. Cell 44 566–581.e8. 10.1016/j.devcel.2018.02.013
    1. Sakane H., Yamamoto H., Kikuchi A. (2010). LRP6 is internalized by Dkk1 to suppress its phosphorylation in the lipid raft and is recycled for reuse. J. Cell Sci. 123(Pt 3) 360–368. 10.1242/jcs.058008
    1. Sato A., Yamamoto H., Sakane H., Koyama H., Kikuchi A. (2010). Wnt5a regulates distinct signalling pathways by binding to Frizzled2. EMBO J. 29 41–54. 10.1038/emboj.2009.322
    1. Schmitt M., Metzger M., Gradl D., Davidson G., Orian-Rousseau V. (2015). CD44 functions in Wnt signaling by regulating LRP6 localization and activation. Cell Death Differ. 22 677–689. 10.1038/cdd.2014.156
    1. Semënov M. V., Tamai K., Brott B. K., Kühl M., Sokol S., He X. (2001). Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr. Biol. 11 951–961. 10.1016/s0960-9822(01)00290-1
    1. Semënov M., Tamai K., He X. (2005). SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J. Biol. Chem. 280 26770–26775. 10.1074/jbc.M504308200
    1. Sezgin E., Levental I., Mayor S., Eggeling C. (2017). The mystery of membrane organization: composition, regulation and roles of lipid rafts. Nat. Rev. Mol. Cell Biol. 18 361–374. 10.1038/nrm.2017.16
    1. Sharma K., Choi S. Y., Zhang Y., Nieland T. J., Long S., Li M., et al. (2013). High-throughput genetic screen for synaptogenic factors: identification of LRP6 as critical for excitatory synapse development. Cell Rep. 5 1330–1341. 10.1016/j.celrep.2013.11.008
    1. Singh R., De Aguiar R. B., Naik S., Mani S., Ostadsharif K., Wencker D., et al. (2013a). LRP6 enhances glucose metabolism by promoting TCF7L2-dependent insulin receptor expression and IGF receptor stabilization in humans. Cell Metab. 17 197–209. 10.1016/j.cmet.2013.01.009
    1. Singh R., Smith E., Fathzadeh M., Liu W., Go G. W., Subrahmanyan L., et al. (2013b). Rare nonconservative LRP6 mutations are associated with metabolic syndrome. Hum. Mutat. 34 1221–1225. 10.1002/humu.22360
    1. Srivastava R., Zhang J., Go G. W., Narayanan A., Nottoli T. P., Mani A. (2015). Impaired LRP6-TCF7L2 activity enhances smooth muscle cell plasticity and causes coronary artery disease. Cell Rep. 13 746–759. 10.1016/j.celrep.2015.09.028
    1. Swiatek W., Kang H., Garcia B. A., Shabanowitz J., Coombs G. S., Hunt D. F., et al. (2006). Negative regulation of LRP6 function by casein kinase I epsilon phosphorylation. J. Biol. Chem. 281 12233–12241. 10.1074/jbc.M510580200
    1. Taelman V. F., Dobrowolski R., Plouhinec J. L., Fuentealba L. C., Vorwald P. P., Gumper I., et al. (2010). Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes. Cell 143 1136–1148. 10.1016/j.cell.2010.11.034
    1. Tahir S. A., Yang G., Goltsov A., Song K. D., Ren C., Wang J., et al. (2013). Caveolin-1-LRP6 signaling module stimulates aerobic glycolysis in prostate cancer. Cancer Res. 73 1900–1911. 10.1158/0008-5472.can-12-3040
    1. Tamai K., Semenov M., Kato Y., Spokony R., Liu C., Katsuyama Y., et al. (2000). LDL-receptor-related proteins in Wnt signal transduction. Nature 407 530–535. 10.1038/35035117
    1. Tamai K., Zeng X., Liu C., Zhang X., Harada Y., Chang Z., et al. (2004). A mechanism for Wnt coreceptor activation. Mol. Cell 13 149–156. 10.1016/s1097-2765(03)00484-2
    1. Tanneberger K., Pfister A. S., Brauburger K., Schneikert J., Hadjihannas M. V., Kriz V., et al. (2011). Amer1/WTX couples Wnt-induced formation of PtdIns(4,5)P2 to LRP6 phosphorylation. EMBO J. 30 1433–1443. 10.1038/emboj.2011.28
    1. Tung E. K., Wong B. Y., Yau T. O., Ng I. O. (2012). Upregulation of the Wnt co-receptor LRP6 promotes hepatocarcinogenesis and enhances cell invasion. PLoS One 7:e36565. 10.1371/journal.pone.0036565
    1. Wan M., Li J., Herbst K., Zhang J., Yu B., Wu X., et al. (2011). LRP6 mediates cAMP generation by G protein-coupled receptors through regulating the membrane targeting of Gα(s). Sci. Signal. 4:ra15. 10.1126/scisignal.2001464
    1. Wan M., Yang C., Li J., Wu X., Yuan H., Ma H., et al. (2008). Parathyroid hormone signaling through low-density lipoprotein-related protein 6. Genes Dev. 22 2968–2979. 10.1101/gad.1702708
    1. Wang H., He L., Ma F., Regan M. M., Balk S. P., Richardson A. L., et al. (2013). SOX9 regulates low density lipoprotein receptor-related protein 6 (LRP6) and T-cell factor 4 (TCF4) expression and Wnt/β-catenin activation in breast cancer. J. Biol. Chem. 288 6478–6487. 10.1074/jbc.M112.419184
    1. Wang L., Chai Y., Li C., Liu H., Su W., Liu X., et al. (2018). Oxidized phospholipids are ligands for LRP6. Bone Res. 6:22. 10.1038/s41413-018-0023-x
    1. Wang X., Jia Y., Fei C., Song X., Li L. (2016). Activation/proliferation-associated protein 2 (Caprin-2) positively regulates CDK14/cyclin Y-mediated lipoprotein receptor-related protein 5 and 6 (LRP5/6) constitutive phosphorylation. J. Biol. Chem. 291 26427–26434. 10.1074/jbc.M116.744607
    1. Wang Y., Yin C., Chen Z., Li Y., Zou Y., Wang X., et al. (2020). Cardiac-specific LRP6 knockout induces lipid accumulation through Drp1/CPT1b pathway in adult mice. Cell Tissue Res. 380 143–153. 10.1007/s00441-019-03126-3
    1. Wehrli M., Dougan S. T., Caldwell K., O’Keefe L., Schwartz S., Vaizel-Ohayon D., et al. (2000). arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Nature 407 527–530. 10.1038/35035110
    1. Wei Q., Yokota C., Semenov M. V., Doble B., Woodgett J., He X. (2007). R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and beta-catenin signaling. J. Biol. Chem. 282 15903–15911. 10.1074/jbc.M701927200
    1. Wu G., Huang H., Garcia Abreu J., He X. (2009). Inhibition of GSK3 phosphorylation of beta-catenin via phosphorylated PPPSPXS motifs of Wnt coreceptor LRP6. PLoS One 4:e4926. 10.1371/journal.pone.0004926
    1. Wu Z., Wei D., Gao W., Xu Y., Hu Z., Ma Z., et al. (2015). TPO-induced metabolic reprogramming drives liver metastasis of colorectal cancer CD110+ tumor-initiating cells. Cell Stem Cell 17 47–59. 10.1016/j.stem.2015.05.016
    1. Xia Z., Wu S., Wei X., Liao Y., Yi P., Liu Y., et al. (2019). Hypoxic ER stress suppresses β-catenin expression and promotes cooperation between the transcription factors XBP1 and HIF1α for cell survival. J. Biol. Chem. 294 13811–13821. 10.1074/jbc.RA119.008353
    1. Yamamoto H., Komekado H., Kikuchi A. (2006). Caveolin is necessary for Wnt-3a-dependent internalization of LRP6 and accumulation of beta-catenin. Dev. Cell 11 213–223. 10.1016/j.devcel.2006.07.003
    1. Yamamoto H., Sakane H., Yamamoto H., Michiue T., Kikuchi A. (2008). Wnt3a and Dkk1 regulate distinct internalization pathways of LRP6 to tune the activation of beta-catenin signaling. Dev. Cell 15 37–48. 10.1016/j.devcel.2008.04.015
    1. Ye Z. J., Go G. W., Singh R., Liu W., Keramati A. R., Mani A. (2012). LRP6 protein regulates low density lipoprotein (LDL) receptor-mediated LDL uptake. J. Biol. Chem. 287 1335–1344. 10.1074/jbc.M111.295287
    1. Yuan Y., Xie X., Jiang Y., Wei Z., Wang P., Chen F., et al. (2017). LRP6 is identified as a potential prognostic marker for oral squamous cell carcinoma via MALDI-IMS. Cell Death Dis. 8:e3035. 10.1038/cddis.2017.433
    1. Zeng X., Huang H., Tamai K., Zhang X., Harada Y., Yokota C., et al. (2008). Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development 135 367–375. 10.1242/dev.013540
    1. Zeng X., Tamai K., Doble B., Li S., Huang H., Habas R., et al. (2005). A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature 438 873–877. 10.1038/nature04185
    1. Zhang J., Li Y., Liu Q., Lu W., Bu G. (2010). Wnt signaling activation and mammary gland hyperplasia in MMTV-LRP6 transgenic mice: implication for breast cancer tumorigenesis. Oncogene 29 539–549. 10.1038/onc.2009.339

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir