DOI: 10.1073/pnas.0409472102. Identification of the Wnt signaling activator leucine-rich repeat in Flightless interaction protein 2 by a genome-wide functional analysis

Identification of the Wnt signaling activator leucine-rich repeat in Flightless interaction protein 2 by a genome-wide functional analysis

10.1073/pnas.0409472102

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

The Wnt signaling pathway acts ubiquitously in metazoans to control various aspects of embryonic development. Wnt ligands bind their receptors Frizzled and low-density lipoprotein receptor-related protein 5/6 and function through Disheveled (Dvl), Axin, adenomatous polyposis coli, glycogen synthase kinase 3β, and casein kinase (CK) 1 to stabilize β-catenin and induce lymphocyte enhancer-binding factor (LEF)/T cell factor (TCF)-dependent transcriptional activities. To identify previously unrecognized Wnt signaling modulators, a genome-wide functional screen was performed using large-scale arrayed cDNA collections. From this screen, both known components and previously uncharacterized regulators of this pathway were identified, including β-catenin, Dvl1, Dvl3, Fbxw-1, Cul1, CK1ε, CK1δ, and γ-catenin. In particular, a previously unrecognized activator, LRRFIP2 (leucine-rich repeat in Flightless interaction protein 2), was found that interacts with Dvl to increase the cellular levels of β-catenin and activate β-catenin/LEF/TCF-dependent transcriptional activity. The function of LRRFIP2 is blocked when a dominant negative Dvl (Xdd1) is coexpressed. Expression of LRRFIP2 in Xenopus embryos induced double axis formation and Wnt target gene expression; a dominant negative form of LRRFIP2 suppresses ectopic Wnt signaling in Xenopus embryos and partially inhibits endogenous dorsal axis formation. These data suggest that LRRFIP2 plays an important role in transducing Wnt signals.

Bibliography

Liu, J., Bang, A. G., Kintner, C., Orth, A. P., Chanda, S. K., Ding, S., & Schultz, P. G. (2005). Identification of the Wnt signaling activator leucine-rich repeat in Flightless interaction protein 2 by a genome-wide functional analysis. Proceedings of the National Academy of Sciences, 102(6), 1927â1932.

Authors 7

Jun Liu (first)
Anne G. Bang (additional)
Chris Kintner (additional)
Anthony P. Orth (additional)
Sumit K. Chanda (additional)
Sheng Ding (additional)
Peter G. Schultz (additional)

References 39 Referenced 69

10.1038/nrg1427
10.1146/annurev.cellbio.20.010403.113126
10.1016/S0092-8674(00)00122-7
10.1126/science.287.5458.1606
10.1016/S1534-5807(03)00165-5
10.1038/35035110
10.1038/35035117
10.1038/35035124
10.1016/j.molcel.2003.08.013
10.1073/pnas.1934839100
10.1073/pnas.1932773100
10.1073/pnas.0308562100
10.1073/pnas.2136685100
10.1126/science.1081403
10.1016/S1097-2765(01)00241-6
Sive H. Grainger R. & Harland R. (2000) Early Development of Xenopus laevis : A Laboratory Manual (Cold Spring Harbor Lab. Press Plainview NY).
Nieuwkoop P. D. & Faber J. (1967) Normal Table of Xenopus laevis (North–Holland Amersterdam).
10.1126/science.275.5307.1784
10.1038/nrm1471
10.1182/blood-2002-08-2652
10.1242/jcs.113.17.2991
10.1128/MCB.18.9.5128
10.1016/S0014-5793(04)00070-5
10.1006/geno.1999.5817
10.1007/s00018-004-4225-6
10.1016/S0959-437X(99)80061-6
10.1073/pnas.071041898
10.1101/gad.869201
10.1016/j.cell.2004.09.019
10.1016/S1534-5807(02)00140-5
10.1038/ncb784
10.1038/ncb716
10.1038/35083016
10.1016/S1097-2765(03)00427-1
10.1038/43830
10.1073/pnas.032468199
10.1016/S0960-9822(96)00750-6
10.1038/34848
10.1016/0012-1606(88)90189-3

Dates

Type	When
Created	20 years, 7 months ago (Jan. 26, 2005, 8:34 p.m.)
Deposited	3 years, 4 months ago (April 25, 2022, 10:51 p.m.)
Indexed	1 month, 4 weeks ago (July 2, 2025, 2:12 p.m.)
Issued	20 years, 7 months ago (Jan. 26, 2005)
Published	20 years, 7 months ago (Jan. 26, 2005)
Published Online	20 years, 7 months ago (Jan. 26, 2005)
Published Print	20 years, 6 months ago (Feb. 8, 2005)

Funders 0

None

BibTeX

@article{Liu_2005, title={Identification of the Wnt signaling activator leucine-rich repeat in Flightless interaction protein 2 by a genome-wide functional analysis}, volume={102}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0409472102}, DOI={10.1073/pnas.0409472102}, number={6}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Liu, Jun and Bang, Anne G. and Kintner, Chris and Orth, Anthony P. and Chanda, Sumit K. and Ding, Sheng and Schultz, Peter G.}, year={2005}, month=jan, pages={1927–1932} }

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  "abstract": "<jats:p>\n            The Wnt signaling pathway acts ubiquitously in metazoans to control various aspects of embryonic development. Wnt ligands bind their receptors Frizzled and low-density lipoprotein receptor-related protein 5/6 and function through Disheveled (Dvl), Axin, adenomatous polyposis coli, glycogen synthase kinase 3\u03b2, and casein kinase (CK) 1 to stabilize \u03b2-catenin and induce lymphocyte enhancer-binding factor (LEF)/T cell factor (TCF)-dependent transcriptional activities. To identify previously unrecognized Wnt signaling modulators, a genome-wide functional screen was performed using large-scale arrayed cDNA collections. From this screen, both known components and previously uncharacterized regulators of this pathway were identified, including \u03b2-catenin, Dvl1, Dvl3, Fbxw-1, Cul1, CK1\u03b5, CK1\u03b4, and \u03b3-catenin. In particular, a previously unrecognized activator, LRRFIP2 (leucine-rich repeat in Flightless interaction protein 2), was found that interacts with Dvl to increase the cellular levels of \u03b2-catenin and activate \u03b2-catenin/LEF/TCF-dependent transcriptional activity. The function of LRRFIP2 is blocked when a dominant negative Dvl (Xdd1) is coexpressed. Expression of LRRFIP2 in\n            <jats:italic>Xenopus</jats:italic>\n            embryos induced double axis formation and Wnt target gene expression; a dominant negative form of LRRFIP2 suppresses ectopic Wnt signaling in\n            <jats:italic>Xenopus</jats:italic>\n            embryos and partially inhibits endogenous dorsal axis formation. These data suggest that LRRFIP2 plays an important role in transducing Wnt signals.\n          </jats:p>",
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