Serine Phosphorylation-regulated Ubiquitination and Degradation of β-Catenin*
- From the ‡Lombardi Cancer Center, Georgetown University Medical Center, Washington, D. C. 20007 and the§NCI, DCBD, National Institutes of Health, Bethesda, Maryland 20892
Abstract
Several lines of evidence suggest that accumulation of cytoplasmic β-catenin transduces an oncogenic signal. We show that β-catenin is ubiquitinated and degraded by the proteosome and that β-catenin stability is regulated by a diacylglycerol-independent protein kinase C-like kinase activity, which is required for β-catenin ubiquitination. We also define a six-amino acid sequence found in both β-catenin and the NF-κB regulatory protein IκBα, which, upon phosphorylation, targets both proteins for ubiquitination. Mutation of a single serine within the ubiquitination targeting sequence prevents ubiquitination of β-catenin. Mutations within the ubiquitination targeting sequence of β-catenin may be oncogenic.
Footnotes
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↵* This work was supported by Grant DAMD17-95-1-5012 from the Department of Defense.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵¶ To whom correspondence should be addressed. Tel.: 202-687-1891; Fax: 202-687-7505; E-mail:byerss{at}gunet.georgetown.edu.
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↵1 The abbreviations used are: Arm, Armadillo; Wg, Wingless; ZW3, Zeste-White 3; GSK3β, glycogen synthase kinase-3β; PKC, protein kinase C; UTS, ubiquitination targeting sequence; ALLN,N-acetyl-Leu-Leu-norleucinal; ALLM,N-Acetyl-Leu-Leu-methional; TPA, 12-O-tetradecanoylphorbol 13-acetate; NEM,N-ethylmaleimide; HMW, high molecular weight; aPKC, atypical protein kinase C; PAGE, polyacrylamide gel electrophoresis; HA, hemagglutinin; EGF, epidermal growth factor; IGF, insulin-like growth factor; DAG, diacylglycerol.
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- Received June 23, 1997.
