title: Functional Characterization of a WWP1/Tiul1 Tumor-derived Mutant Reveals a Paradigm of Its Constitutive Activation in Human Cancer.
abstract: Although E3 ubiquitin ligases are deemed to play key roles in normal cell function and homeostasis, whether their alterations contribute to cancer pathogenesis remains unclear. In this study, we sought to investigate potential mechanisms that govern WWP1/Tiul1 (WWP1) ubiquitin ligase activity, focusing on its ability to trigger degradation of TGFβ type I receptor (TβRI) in conjunction with Smad7. Our data reveal that the WWP1 protein is very stable at steady states because its autopolyubiquitination activity is silenced due to an intra-interaction between the C2 and/or WW and Hect domains that favors WWP1 monoubiquitination at the expense of its polyubiquitination or polyubiquitination of TβRI. Upon binding of WWP1 to Smad7, this functional interplay is disabled, switching its monoubiquitination activity toward a polyubiquitination activity, thereby driving its own degradation and that of TβRI as well. Intriguingly, a WWP1 point mutation found in human prostate cancer disrupts this regulatory mechanism by relieving the inhibitory effects of C2 and WW on Hect and thereby causing WWP1 hyperactivation. That cancer-driven alteration of WWP1 culminates in excessive TβRI degradation and attenuated TGFβ cytostatic signaling, a consequence that could conceivably confer tumorigenic properties to WWP1.
authors.affiliation: Université Pierre et Marie Curie, Université Paris 06, Paris 75005, France; INSERM UMR S 938, Laboratory of Cell Signaling and Carcinogenesis, Paris 75012, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Courivaud
authors.affiliation: Université Pierre et Marie Curie, Université Paris 06, Paris 75005, France; INSERM UMR S 938, Laboratory of Cell Signaling and Carcinogenesis, Paris 75012, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ferrand
authors.affiliation: Cancer Institute and Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi 39216.
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Elkhattouti
authors.affiliation: Cancer Institute and Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi 39216.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Université Pierre et Marie Curie, Université Paris 06, Paris 75005, France; INSERM UMR S 938, Laboratory of Cell Signaling and Carcinogenesis, Paris 75012, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Levy
authors.affiliation: Université Pierre et Marie Curie, Université Paris 06, Paris 75005, France; INSERM UMR S 938, Laboratory of Cell Signaling and Carcinogenesis, Paris 75012, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Ferrigno
authors.affiliation: Université Pierre et Marie Curie, Université Paris 06, Paris 75005, France; INSERM UMR S 938, Laboratory of Cell Signaling and Carcinogenesis, Paris 75012, France; Cancer Institute and Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi 39216.
authors.forename: Azeddine
authors.initials: A
authors.lastname: Atfi
authors.affiliation: Université Pierre et Marie Curie, Université Paris 06, Paris 75005, France; INSERM UMR S 938, Laboratory of Cell Signaling and Carcinogenesis, Paris 75012, France. Electronic address: celine.prunier@inserm.fr.
authors.forename: Céline
authors.initials: C
authors.lastname: Prunier
mesh_terms: D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D017354:Point Mutation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018125:Receptors, Transforming Growth Factor beta; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1; C471642:WWP1 protein, human; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: E3 ubiquitin ligase; WWP1/Tiul1; cancer biology; enzyme mutation; protein degradation; signaling; transforming growth factor β (TGF-β)