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  • Original Paper
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Truncated mutants of the putative Wnt receptor LRP6/Arrow can stabilize β-catenin independently of Frizzled proteins

Oncogene volume 23, pages 4873–4884 (2004)Cite this article

Abstract

Secreted signaling proteins of the Wnt family are known to regulate a diverse range of developmental processes, and their signaling pathway through β-catenin is frequently activated in cancer. The identification of both Frizzled and LRP5/6 (LRP: low-density lipoprotein receptor-related protein) proteins as components of cell-surface receptors for Wnt proteins has raised questions about their individual functions. We have investigated this issue through a structure–function analysis of Frizzled and LRP proteins that have been implicated in Wnt1 signaling. Consistent with other reports, we find that LRP6/Arrow proteins deleted for their extracellular domain are able to activate the Wnt/β-catenin signaling pathway. Importantly, our results demonstrate that this signaling from LRP6/Arrow derivatives can occur in a Frizzled- and ligand-independent manner. Furthermore, we show that the PPSP motifs within the intracellular domain of LRP6 are required for signaling. In contrast to results with LRP6, overexpression of Frizzled proteins did not activate the pathway. Based on evidence of ligand binding to both Frizzled and LRP6, current models suggest that both proteins are components of a Wnt receptor complex that signals to β-catenin. In light of these models, our data imply that LRP5/6/Arrow proteins constitute the distal signal-initiating component of these receptors. The results also support the notion that LRP5/6 are candidate oncogenes.

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Abbreviations

APC:

adenomatous polyposis coli

Arr:

Arrow

CRD:

cysteine-rich domain

EGF:

epidermal growth factor

Fzd/fz:

Frizzled

GSK-3β:

glycogen synthase kinase-3β

LDL:

low-density lipoprotein

LDLR:

LDL receptor

LRP:

LDLR- related protein

S2:

Schneider 2

TCF:

T-cell factor

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Acknowledgements

We are grateful to Drs Fred Hess, Hans Clevers, Vincent Zecchini, Simon Kidd, Robert Nissenson, and Jeremy Nathans for supplying plasmids. We also thank C Dong, M Semenov, and M Goll for contributions to the early phases of analysing Frizzled constructs, and K Tolle for technical assistance. The mouse anti-Armadillo antibody N2 7A1 was produced in the laboratory of Dr Eric Wieschaus and was obtained from the Developmental Studies Hybridoma Bank (DSHB). The DSHB was developed under the auspices of the NICHD and is maintained by The University of Iowa, Department of Biological Sciences, Iowa City, IA 52242, USA.

This work was supported by US Army Medical Research and Materiel Command fellowships DAMD17-99-1-9388 (to KB) and DAMD17-02-1-0359 (to LACS), by NIH MSTP Grant GM67739, by a fellowship from the Ministerio de Educacion, Cultura y Deportes of Spain (to JMGS), and by NIH Grant CA47207 (to AMCB).

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  1. Keith Brennan

    Present address: School of Biological Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK

Authors and Affiliations

  1. Strang Cancer Research Laboratory at The Rockefeller University, 1230 York Avenue, New York, 10021, NY, USA

    Keith Brennan, José M Gonzalez-Sancho, Leslie A Castelo-Soccio, Louise R Howe & Anthony MC Brown

  2. Department of Cell and Developmental Biology, Weill Medical College of Cornell University, 1300 York Avenue, New York,, 10021, NY, USA

    Keith Brennan, José M Gonzalez-Sancho, Leslie A Castelo-Soccio, Louise R Howe & Anthony MC Brown

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Correspondence to Anthony MC Brown.

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Brennan, K., Gonzalez-Sancho, J., Castelo-Soccio, L. et al. Truncated mutants of the putative Wnt receptor LRP6/Arrow can stabilize β-catenin independently of Frizzled proteins. Oncogene 23, 4873–4884 (2004). https://doi.org/10.1038/sj.onc.1207642

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