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PMID:20059950

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Citation

Suizu, F, Hiramuki, Y, Okumura, F, Matsuda, M, Okumura, AJ, Hirata, N, Narita, M, Kohno, T, Yokota, J, Bohgaki, M, Obuse, C, Hatakeyama, S, Obata, T and Noguchi, M (2009) The E3 ligase TTC3 facilitates ubiquitination and degradation of phosphorylated Akt. Dev. Cell 17:800-10

Abstract

The serine threonine kinase Akt is a core survival factor that underlies a variety of human diseases. Although regulatory phosphorylation and dephosphorylation have been well documented, the other posttranslational mechanisms that modulate Akt activity remain unclear. We show here that tetratricopeptide repeat domain 3 (TTC3) is an E3 ligase that interacts with Akt. TTC3 contains a canonical RING finger motif, a pair of tetratricopeptide motifs, a putative Akt phosphorylation site, and nuclear localization signals, and is encoded by a gene within the Down syndrome (DS) critical region on chromosome 21. TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus. Moreover, DS cells exhibit elevated TTC3 expression, reduced phosphorylated Akt, and accumulation in the G(2)M phase, which can be reversed by TTC3 siRNA or Myr-Akt. Thus, interaction between TTC3 and Akt may contribute to the clinical symptoms of DS.

Links

PubMed Online version:10.1016/j.devcel.2009.09.007

Keywords

Cell Line; Cells, Cultured; Down Syndrome/metabolism; Humans; Immunoprecipitation; Phosphorylation; Proteasome Endopeptidase Complex/metabolism; Protein Interaction Mapping; Proto-Oncogene Proteins c-akt/metabolism; Ubiquitin-Protein Ligases/metabolism; Ubiquitination

Significance

Annotations

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

HUMAN:AKT1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P53804

F

Seeded From UniProt

complete

HUMAN:AKT2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P53804

F

Seeded From UniProt

complete

HUMAN:TTC3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P31751

F

Seeded From UniProt

complete

HUMAN:TTC3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Y243

F

Seeded From UniProt

complete

HUMAN:TTC3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P31749

F

Seeded From UniProt

complete

HUMAN:AKT3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P53804

F

Seeded From UniProt

complete

HUMAN:AKT2

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TTC3

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TTC3

enables

GO:0004842: ubiquitin-protein transferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TTC3

involved_in

GO:0006511: ubiquitin-dependent protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TTC3

involved_in

GO:0070936: protein K48-linked ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:Q05BV0

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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