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PMID:11533658

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Citation

Ryo, A, Nakamura, M, Wulf, G, Liou, YC and Lu, KP (2001) Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC. Nat. Cell Biol. 3:793-801

Abstract

Phosphorylation on a serine or threonine residue preceding proline (Ser/Thr-Pro) is a key regulatory mechanism, and the conformation of certain phosphorylated Ser/Thr-Pro bonds is regulated specifically by the prolyl isomerase Pin1. Whereas the inhibition of Pin1 induces apoptosis, Pin1 is strikingly overexpressed in a subset of human tumours. Here we show that Pin1 regulates beta-catenin turnover and subcellular localization by interfering with its interaction with adenomatous polyposis coli protein (APC). A differential-display screen reveals that Pin1 increases the transcription of several beta-catenin target genes, including those encoding cyclin D1 and c-Myc. Manipulation of Pin1 levels affects the stability of beta-catenin in vitro. Furthermore, beta-catenin levels are decreased in Pin1-deficient mice but are increased and correlated with Pin1 overexpression in human breast cancer. Pin1 directly binds a phosphorylated Ser-Pro motif next to the APC-binding site in beta-catenin, inhibits its interaction with APC and increases its translocation into the nucleus. Thus, Pin1 is a novel regulator of beta-catenin signalling and its overexpression might contribute to the upregulation of beta-catenin in tumours such as breast cancer, in which APC or beta-catenin mutations are not common.

Links

PubMed Online version:10.1038/ncb0901-793

Keywords

Adenomatous Polyposis Coli/enzymology; Adenomatous Polyposis Coli/genetics; Adenomatous Polyposis Coli/pathology; Amino Acid Sequence; Amino Acid Substitution; Cadherins/metabolism; Cell Nucleus/metabolism; Cytoskeletal Proteins/chemistry; Cytoskeletal Proteins/genetics; Cytoskeletal Proteins/metabolism; Gene Expression Regulation; Genes, Reporter; HeLa Cells; Humans; Kinetics; Mutagenesis, Site-Directed; Peptidylprolyl Isomerase/chemistry; Peptidylprolyl Isomerase/genetics; Peptidylprolyl Isomerase/metabolism; Phosphorylation; Phosphothreonine/metabolism; Protein Transport; Recombinant Fusion Proteins/biosynthesis; Recombinant Proteins/chemistry; Recombinant Proteins/metabolism; Trans-Activators; Transfection; beta Catenin

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:P25054

F

Seeded From UniProt

complete

HUMAN:PIN1

involved_in

GO:0032091: negative regulation of protein binding

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P25054)
  • has_input:(UniProtKB:P35222)

Seeded From UniProt

complete

HUMAN:PIN1

enables

GO:0003755: peptidyl-prolyl cis-trans isomerase activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PIN1

involved_in

GO:0042177: negative regulation of protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P35222)

Seeded From UniProt

complete

HUMAN:PIN1

enables

GO:0050815: phosphoserine residue binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:P35222)

Seeded From UniProt

complete

HUMAN:PIN1

involved_in

GO:0050821: protein stabilization

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P35222)

Seeded From UniProt

complete

HUMAN:PIN1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P24385)|has_input:(UniProtKB:P01106)|has_input:(UniProtKB:Q03181)|has_input:(UniProtKB:P02751)

Seeded From UniProt

complete

HUMAN:PIN1

involved_in

GO:1900180: regulation of protein localization to nucleus

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P35222)

Seeded From UniProt

complete

MOUSE:PIN1

involved_in

GO:0050821: protein stabilization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:Q02248)

Seeded From UniProt

complete

HUMAN:CTNB1

enables

GO:0019899: enzyme binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13526

F

Seeded From UniProt

complete

MOUSE:PIN1

involved_in

GO:0050821: protein stabilization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

stabilizes:(UniProtKB:Q02248)

Seeded From UniProt

complete

HUMAN:PIN1

enables

GO:0008013: beta-catenin binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35222

F

Seeded From UniProt

complete

HUMAN:PIN1

involved_in

GO:0042177: negative regulation of protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(UniProtKB:P35222)

Seeded From UniProt

complete

HUMAN:PIN1

involved_in

GO:0050821: protein stabilization

ECO:0000314: direct assay evidence used in manual assertion

P

stabilizes:(UniProtKB:P35222)

Seeded From UniProt

complete

HUMAN:PIN1

enables

GO:0050815: phosphoserine residue binding

ECO:0000314: direct assay evidence used in manual assertion

F

has_direct_input:(UniProtKB:P35222)

Seeded From UniProt

complete

HUMAN:PIN1

involved_in

GO:0090263: positive regulation of canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PIN1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

regulates_transcription_of:(ENSEMBL:ENSG00000110092)|regulates_transcription_of:(ENSEMBL:ENSG00000136997)|regulates_transcription_of:(ENSEMBL:ENSG00000112033)|regulates_transcription_of:(ENSEMBL:ENSG00000115414)

Seeded From UniProt

complete

HUMAN:PIN1

involved_in

GO:0032091: negative regulation of protein binding

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_regulation_target:(UniProtKB:P25054)
  • has_regulation_target:(UniProtKB:P35222)

Seeded From UniProt

complete

HUMAN:PIN1

involved_in

GO:1900180: regulation of protein localization to nucleus

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(UniProtKB:P35222)

Seeded From UniProt

complete

HUMAN:PIN1

enables

GO:0003755: peptidyl-prolyl cis-trans isomerase activity

ECO:0000304: author statement supported by traceable reference used in manual assertion


F

causally_upstream_of:(GO:0006355)|causally_upstream_of:(GO:0051726)|causally_upstream_of:(GO:0023051)|causally_upstream_of:(GO:0042176)|causally_upstream_of:(GO:0042325)

Seeded From UniProt

complete

HUMAN:PIN1

involved_in

GO:0000413: protein peptidyl-prolyl isomerization

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:APC

enables

GO:0008013: beta-catenin binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35222

F

Seeded From UniProt

complete


See also

References

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