PMID:11533658

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
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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

References

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