title: Cathepsin-B-mediated cleavage of Disabled-2 regulates TGF-β-induced autophagy.
abstract: Transforming growth factor-β (TGF-β) induces the expression of Disabled-2 (Dab2), an endocytic adaptor and tumour suppressor, concomitant with the induction of an epithelial-mesenchymal transition (EMT) in mammary epithelial cells. Here we show that following TGF-β-mediated EMT, sustained TGF-β treatment leads to proteolytic degradation of Dab2 by cathepsin B (CTSB), loss of the mesenchymal phenotype and induction of autophagy. CTSB inhibition or expression of a CTSB-resistant Dab2 mutant maintains Dab2 expression and shifts long-term TGF-β-treated cells from autophagy to apoptosis. We further show that Dab2 interacts with Beclin-1 to promote casein-kinase-2-mediated phosphorylation of Beclin-1, preventing Beclin-1-Vps34 interaction and subsequent autophagosome assembly. Thus, CTSB-mediated degradation of Dab2 allows Beclin-1-Vps34 induction of autophagy, whereas sustained Dab2 expression prevents autophagy and promotes apoptosis by stabilizing the pro-apoptotic Bim protein. In vivo studies suggest that Dab2-mediated regulation of autophagy modulates chemotherapeutic resistance and tumour metastasis.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Alec N
authors.initials: AN
authors.lastname: Woosley
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.|Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Nageswaran
authors.initials: N
authors.lastname: Sivalingam
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Sneha
authors.initials: S
authors.lastname: Natarajan
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.|Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Howe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002401:Cathepsin B / Q000378:metabolism*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; C478773:Dab2 protein, mouse; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; C533912:CTSB protein, human; D002401:Cathepsin B; C533915:Ctsb protein, mouse