The human F box protein β-Trcp associates with the Cul1/Skp1 complex and regulates the stability of β-catenin

Abstract

Ubiquitin-conjugation targets numerous cellular regulators for proteasome-mediated degradation. Thus, the identi®cation of ubiquitin ligases and their physiological substrates is crucially important, especially for those cases in which aberrant levels of regulatory proteins (e.g., b-catenin, p27) result from a deregulated ubiquitination pathway. In yeast, the proteolysis of several G1 regulators is controlled by ubiquitin ligases (or SCFs) formed by three subunits: Skp1, Cul A (Cdc53), and one of many F-box proteins. Speci®c

Wnt signaling in disease and in development

“…The interaction between these kinases and β-catenin is facilitated by the scaffolding proteins, Axin and APC [14,15]. Together, these proteins form α-catenin 'degradation complex,' which allows phosphorylated β-catenin to be recognized by β-TrCP, targeted for ubiquitination, and degraded by the proteosome [16][17][18].…”

Controlled levels of canonical Wnt signaling are required for neural crest migration

“…Phosphorylated β-catenin becomes ubiquitylated by β-TrCP and is targeted for degradation (Aberle et al, 1997;Orford et al, 1997;Kitagawa et al, 1999;Latres et al, 1999;Liu et al, 1999) (Fig.1.3.1A). Upon binding of canonical Wnt ligands to their coreceptors Frizzleds (Fz) and low-density-lipoprotein-related protein5/6 (Lrp5/6) on the cell surface MacDonald and He, 2012) Lrp5/6 becomes dually phosphorylated by CK1 and GSK-3β and inactivates the destruction complex by recruitment of Axin to the plasma membrane (Davidson et al, 2005;Zeng et al, 2005).…”

Differential interaction of plakoglobin and β-catenin with the ubiquitin-proteasome system

“…The targeting of b-catenin for degradation involves the phosphorylation of its N-terminus by glycogen synthase kinase 3b (GSK) (Aberle et al, 1997;Yost et al, 1996) which occurs in a multi-protein complex consisting of b-catenin, GSK, the adenoma-tous polyposis coli (APC) tumor suppressor protein and axin/conductin Rubinfeld et al, 1996;Zeng et al, 1997;Ikeda et al, 1998;Behrens et al, 1998;Yamamoto et al, 1998). This complex associates with the ubiquitin ligase, b-TrCP (b-transducin repeat-containing protein) that recognizes the N-terminally phosphorylated forms of bcatenin and regulates its ubiquitination and degradation by the proteasome (Winston et al, 1999;Liu et al, 1999;Latres et al, 1999;Hart et al, 1999;Kitagawa et al, 1999). b-TrCP associates through its F-box with Cul1/Skp1/ROC1 forming the modular ubiquitin ligase SCF complex (Latres et al, 1999;Tan et al, 1999) and via its WD repeat motif with the phosphorylated bcatenin (Winston et al, 1999;Liu et al, 1999;Hart et al, 1999), thus forming a multimolecular complex consisting of b-TrCP/b-catenin/Axin/GSK/APC (Liu et al, 1999;Kitagawa et al, 1999).…”

“…This complex associates with the ubiquitin ligase, b-TrCP (b-transducin repeat-containing protein) that recognizes the N-terminally phosphorylated forms of bcatenin and regulates its ubiquitination and degradation by the proteasome (Winston et al, 1999;Liu et al, 1999;Latres et al, 1999;Hart et al, 1999;Kitagawa et al, 1999). b-TrCP associates through its F-box with Cul1/Skp1/ROC1 forming the modular ubiquitin ligase SCF complex (Latres et al, 1999;Tan et al, 1999) and via its WD repeat motif with the phosphorylated bcatenin (Winston et al, 1999;Liu et al, 1999;Hart et al, 1999), thus forming a multimolecular complex consisting of b-TrCP/b-catenin/Axin/GSK/APC (Liu et al, 1999;Kitagawa et al, 1999). b-TrCP and its Drosophila homolog Slimb were implicated in the regulation of wnt/wg signaling (Jiang and Struhl, 1998) and the DF-b-TrCP mutant, lacking the F-box, was shown to induce axis duplication in Xenopus (Marikawa and Elinson, 1998;Liu et al, 1999), and loss of function mutations in Slimb, induce the accumulation of armadillo in Drosophila (Jiang and Struhl, 1998).…”