title: HectD1 E3 ligase modifies adenomatous polyposis coli (APC) with polyubiquitin to promote the APC-axin interaction.
abstract: The adenomatous polyposis coli (APC) protein functions as a negative regulator of the Wnt signaling pathway. In this capacity, APC forms a "destruction complex" with Axin, CK1α, and GSK3β to foster phosphorylation of the Wnt effector β-catenin earmarking it for Lys-48-linked polyubiquitylation and proteasomal degradation. APC is conjugated with Lys-63-linked ubiquitin chains when it is bound to Axin, but it is unclear whether this modification promotes the APC-Axin interaction or confers upon APC an alternative function in the destruction complex. Here we identify HectD1 as a candidate E3 ubiquitin ligase that modifies APC with Lys-63 polyubiquitin. Knockdown of HectD1 diminished APC ubiquitylation, disrupted the APC-Axin interaction, and augmented Wnt3a-induced β-catenin stabilization and signaling. These results indicate that HectD1 promotes the APC-Axin interaction to negatively regulate Wnt signaling.
authors.affiliation: Department of Cancer Targets, Genentech Inc., South San Francisco, California 94080, USA. tran.hoanh@gene.com
authors.forename: Hoanh
authors.initials: H
authors.lastname: Tran
authors.forename: Daisy
authors.initials: D
authors.lastname: Bustos
authors.forename: Ronald
authors.initials: R
authors.lastname: Yeh
authors.forename: Bonnee
authors.initials: B
authors.lastname: Rubinfeld
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lam
authors.forename: Stephanie
authors.initials: S
authors.lastname: Shriver
authors.forename: Inna
authors.initials: I
authors.lastname: Zilberleyb
authors.forename: Michelle W
authors.initials: MW
authors.lastname: Lee
authors.forename: Lilian
authors.initials: L
authors.lastname: Phu
authors.forename: Anjali A
authors.initials: AA
authors.lastname: Sarkar
authors.forename: Irene E
authors.initials: IE
authors.lastname: Zohn
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Wertz
authors.forename: Donald S
authors.initials: DS
authors.lastname: Kirkpatrick
authors.forename: Paul
authors.initials: P
authors.lastname: Polakis
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D025821:Polyubiquitin / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; D025821:Polyubiquitin; D044767:Ubiquitin-Protein Ligases; C555337:APC protein, human; C000588989:HECTD1 protein, human