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PMID:18936100

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Citation

Gao, X, Wen, J, Zhang, L, Li, X, Ning, Y, Meng, A and Chen, YG (2008) Dapper1 is a nucleocytoplasmic shuttling protein that negatively modulates Wnt signaling in the nucleus. J. Biol. Chem. 283:35679-88

Abstract

Wnt signaling, via the activation of the canonical beta-catenin and lymphoid enhancer factor (LEF)/T-cell factor pathway, plays an important role in embryogenesis and cancer development by regulating the expression of genes involved in cell proliferation, differentiation, and survival. Dapper (Dpr), as a Dishevelled interactor, has been suggested to modulate Wnt signaling by promoting Dishevelled degradation. Here, we provide evidence that Dpr1 shuttles between the cytoplasm and the nucleus. Although overexpressed Dpr1 was mainly found in the cytoplasm, endogenous Dpr1 was localized over the cell, and Wnt1 induced its nuclear export. Treatment with leptomycin B induced nuclear accumulation of both endogenous and overexpressed Dpr1. We further identified the nuclear localization signal and the nuclear export signal within Dpr1. Using reporter assay and in vivo zebrafish embryo assay, we demonstrated that the forced nuclearly localized Dpr1 possessed the ability to antagonize Wnt signaling. Dpr1 interacted with beta-catenin and LEF1 and disrupted their complex formation. Furthermore, Dpr1 could associate with histone deacetylase 1 (HDAC1) and enhance the LEF1-HDAC1 interaction. Together, our findings suggest that Dpr1 negatively modulates the basal activity of Wnt/beta-catenin signaling in the nucleus by keeping LEF1 in the repressive state. Thus, Dpr1 controls Wnt/beta-catenin signaling in both the cytoplasm and the nucleus.

Links

PubMed Online version:10.1074/jbc.M804088200

Keywords

Active Transport, Cell Nucleus/drug effects; Active Transport, Cell Nucleus/physiology; Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; Animals; Antibiotics, Antineoplastic/pharmacology; Cell Nucleus/genetics; Cell Nucleus/metabolism; Cytoplasm/genetics; Cytoplasm/metabolism; Fatty Acids, Unsaturated/pharmacology; HeLa Cells; Histone Deacetylase 1; Histone Deacetylases/genetics; Histone Deacetylases/metabolism; Humans; Lymphoid Enhancer-Binding Factor 1/genetics; Lymphoid Enhancer-Binding Factor 1/metabolism; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Signal Transduction/drug effects; Signal Transduction/physiology; Wnt1 Protein/genetics; Wnt1 Protein/metabolism; Zebrafish/genetics; Zebrafish/metabolism; beta Catenin/genetics; beta Catenin/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CTNB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9NYF0

F

Seeded From UniProt

complete

HUMAN:CTNB1

enables

GO:0061629: RNA polymerase II-specific DNA-binding transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UJU2

F

Seeded From UniProt

complete

HUMAN:HDAC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9NYF0

F

Seeded From UniProt

complete

HUMAN:HDAC1

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04426,UniProtKB:Q9NYF0

P

Seeded From UniProt

complete

HUMAN:HDAC1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:HDAC1

enables

GO:0061629: RNA polymerase II-specific DNA-binding transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UJU2

F

Seeded From UniProt

complete

HUMAN:HDAC1

involved_in

GO:0090090: negative regulation of canonical Wnt signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04426,UniProtKB:Q9NYF0

P

Seeded From UniProt

complete

HUMAN:DACT1

enables

GO:0008013: beta-catenin binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35222

F

Seeded From UniProt

complete

HUMAN:DACT1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:DACT1

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:DACT1

involved_in

GO:0032092: positive regulation of protein binding

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q13547,UniProtKB:Q9UJU2

P

Seeded From UniProt

complete

HUMAN:DACT1

involved_in

GO:0032091: negative regulation of protein binding

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P35222,UniProtKB:Q9UJU2

P

Seeded From UniProt

complete

HUMAN:DACT1

enables

GO:0042826: histone deacetylase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13547

F

Seeded From UniProt

complete

HUMAN:DACT1

enables

GO:0061629: RNA polymerase II-specific DNA-binding transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UJU2

F

Seeded From UniProt

complete

HUMAN:DACT1

involved_in

GO:0090090: negative regulation of canonical Wnt signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04426

P

Seeded From UniProt

complete

HUMAN:DACT1

involved_in

GO:1904864: negative regulation of beta-catenin-TCF complex assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DACT1

involved_in

GO:1903364: positive regulation of cellular protein catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(GO:0005737)
  • has_input:(UniProtKB:O14641)

Seeded From UniProt

complete

HUMAN:DACT1

enables

GO:0008013: beta-catenin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DACT1

involved_in

GO:0030178: negative regulation of Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DACT1

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DACT1

involved_in

GO:0060828: regulation of canonical Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DACT1

involved_in

GO:2000134: negative regulation of G1/S transition of mitotic cell cycle

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LEF1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9NYF0

F

Seeded From UniProt

complete

HUMAN:LEF1

enables

GO:0008013: beta-catenin binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35222

F

Seeded From UniProt

complete

HUMAN:LEF1

part_of

GO:1990907: beta-catenin-TCF complex

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35222

C

Seeded From UniProt

complete

HUMAN:LEF1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:LEF1

enables

GO:0042826: histone deacetylase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13547

F

Seeded From UniProt

complete

HUMAN:CTNB1

part_of

GO:1990907: beta-catenin-TCF complex

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UJU2

C

Seeded From UniProt

complete

HUMAN:CTNB1

enables

GO:0001085: RNA polymerase II transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UJU2

F

occurs_in:(GO:0005634)

Seeded From UniProt

complete

HUMAN:HDAC1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:HDAC1

enables

GO:0001085: RNA polymerase II transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UJU2

F

occurs_in:(GO:0005634)

Seeded From UniProt

complete

HUMAN:HDAC1

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04426,UniProtKB:Q9NYF0

P

occurs_in:(GO:0005634)

Seeded From UniProt

complete

HUMAN:HDAC1

involved_in

GO:0090090: negative regulation of canonical Wnt signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04426,UniProtKB:Q9NYF0

P

occurs_in:(GO:0005634)

Seeded From UniProt

complete

Notes

See also

References

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