Identification of the Wnt signaling activator leucine-rich repeat in Flightless interaction protein 2 by a genome-wide functional analysis.
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 3beta, and casein kinase (CK) 1 to stabilize beta-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 beta-catenin, Dvl1, Dvl3, Fbxw-1, Cul1, CK1epsilon, CK1delta, and gamma-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 beta-catenin and activate beta-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.
Liu
Jun
J
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Bang
Anne G
AG
Kintner
Chris
C
Orth
Anthony P
AP
Chanda
Sumit K
SK
Ding
Sheng
S
Schultz
Peter G
PG
D048868:Adaptor Proteins, Signal Transducing; D017503:Adenovirus E3 Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019521:Body Patterning; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D000072261:Dishevelled Proteins; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D015894:Genome, Human; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D017503:Adenovirus E3 Proteins; D002352:Carrier Proteins; C000606586:DVL1 protein, Xenopus; C000606578:DVL1 protein, human; C000606584:DVL3 protein, human; D000072261:Dishevelled Proteins; D036341:Intercellular Signaling Peptides and Proteins; C120550:LRRFIP2 protein, human; D010750:Phosphoproteins; D020033:Protein Isoforms; D051153:Wnt Proteins; D029867:Xenopus Proteins