Curr Biol 1999,
PMID: 10074433
Hart, M; Concordet, J P; Lassot, I; Albert, I; del los Santos, R; Durand, H; Perret, C; Rubinfeld, B; Margottin, F; Benarous, R; Polakis, P
Defects in beta-catenin regulation contribute to the neoplastic transformation of mammalian cells. Dysregulation of beta-catenin can result from missense mutations that affect critical sites of phosphorylation by glycogen synthase kinase 3beta (GSK3beta). Given that phosphorylation can regulate targeted degradation of beta-catenin by the proteasome, beta-catenin might interact with an E3 ubiquitin ligase complex containing an F-box protein, as is the case for certain cell cycle regulators. Accordingly, disruption of the Drosophila F-box protein Slimb upregulates the beta-catenin homolog Armadillo. We reasoned that the human homologs of Slimb - beta-TrCP and its isoform beta-TrCP2 (KIAA0696) - might interact with beta-catenin. We found that the binding of beta-TrCP to beta-catenin was direct and dependent upon the WD40 repeat sequences in beta-TrCP and on phosphorylation of the GSK3beta sites in beta-catenin. Endogenous beta-catenin and beta-TrCP could be coimmunoprecipitated from mammalian cells. Overexpression of wild-type beta-TrCP in mammalian cells promoted the downregulation of beta-catenin, whereas overexpression of a dominant-negative deletion mutant upregulated beta-catenin protein levels and activated signaling dependent on the transcription factor Tcf. In contrast, beta-TrCP2 did not associate with beta-catenin. We conclude that beta-TrCP is a component of an E3 ubiquitin ligase that is responsible for the targeted degradation of phosphorylated beta-catenin.
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Text Mining Data
Dashed line = No text mining data
Manually curated Databases
-
IRef Biogrid Interaction:
CTNNB1
—
GSK3B
(direct interaction, enzymatic study)
-
IRef Biogrid Interaction:
BTRC
—
SKP1
(direct interaction, two hybrid)
-
IRef Biogrid Interaction:
BTRC
—
APC
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
CTNNB1
—
BTRC
(direct interaction, two hybrid)
-
IRef Biogrid Interaction:
CTNNB1
—
BTRC
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
CTNNB1
—
BTRC
(direct interaction, pull down)
-
IRef Biogrid Interaction:
CTNNB1
—
APC2
(direct interaction, two hybrid)
-
IRef Innatedb Interaction:
BTRC
—
APC
(unknown, -)
-
IRef Innatedb Interaction:
BTRC
—
CTNNB1
(unknown, -)
-
NCI Pathway Database Degradation of beta catenin:
beta catenin (CTNNB1)
→
APC/beta catenin complex (APC-CTNNB1)
(modification, collaborate)
Evidence: assay, physical interaction
-
NCI Pathway Database Degradation of beta catenin:
beta catenin (CTNNB1)
→
APC (APC)
(modification, collaborate)
Evidence: assay, physical interaction
-
NCI Pathway Database Degradation of beta catenin:
SCF complex (BTRC-SKP1-CUL1)
→
APC/beta catenin complex (APC-CTNNB1)
(modification, activates)
Evidence: assay, physical interaction
-
NCI Pathway Database Degradation of beta catenin:
SCF complex (BTRC-SKP1-CUL1)
→
APC (APC)
(modification, activates)
Evidence: assay, physical interaction
-
NCI Pathway Database Degradation of beta catenin:
APC/beta catenin complex (APC-CTNNB1)
→
APC (APC)
(modification, collaborate)
Evidence: assay, physical interaction
In total, 14 gene pairs are associated to this article in curated databases