AMBRA1 Promotes TGFβ Signaling via Nonproteolytic Polyubiquitylation of Smad4.
Adaptor Proteins, Signal Transducing
/ genetics
Animals
Carrier Proteins
/ metabolism
Cell Line, Tumor
Cells, Cultured
Disease Models, Animal
Epithelial-Mesenchymal Transition
/ genetics
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Heterografts
Humans
Mice
Mutation
Neoplasms
/ etiology
Protein Binding
Signal Transduction
Smad4 Protein
/ genetics
Substrate Specificity
Transforming Growth Factor beta
/ metabolism
Ubiquitination
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
01 10 2021
01 10 2021
Historique:
received:
07
02
2021
revised:
22
06
2021
accepted:
03
08
2021
pubmed:
8
8
2021
medline:
4
1
2022
entrez:
7
8
2021
Statut:
ppublish
Résumé
Transforming growth factor β (TGFβ) is prometastatic in advanced cancers and its biological activities are mainly mediated by the Smad family of proteins. Smad4 is the central signal transducer and transcription factor in the TGFβ pathway, yet the underlying mechanisms that govern transcriptional activities of Smad4 are not fully understood. Here, we show that AMBRA1, a member of the DDB1 and CUL4-associated factor (DCAF) family of proteins, serves as the substrate receptor for Smad4 in the CUL4-RING (CRL4) ubiquitin ligase complex. The CRL4-AMBRA1 ubiquitin ligase mediates nonproteolytic polyubiquitylation of Smad4 to enhance its transcriptional functions. Consequently, AMBRA1 potentiated TGFβ signaling and critically promoted TGFβ-induced epithelial-to-mesenchymal transition, migration, and invasion of breast cancer cells. Mouse models of breast cancer demonstrated that AMBRA1 promotes metastasis. Collectively, these results show that CRL4-AMBRA1 facilitates TGFβ-driven metastasis by increasing Smad4 polyubiquitylation, suggesting AMBRA1 may serve as a new therapeutic target in metastatic breast cancer. SIGNIFICANCE: This study identifies AMBRA1 as a novel regulator of TGFβ signaling and breast cancer metastasis, supporting further exploration of AMBRA1 as a target for cancer therapy.
Identifiants
pubmed: 34362797
pii: 0008-5472.CAN-21-0431
doi: 10.1158/0008-5472.CAN-21-0431
doi:
Substances chimiques
AMBRA1 protein, human
0
Adaptor Proteins, Signal Transducing
0
Carrier Proteins
0
SMAD4 protein, human
0
Smad4 Protein
0
Transforming Growth Factor beta
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5007-5020Informations de copyright
©2021 American Association for Cancer Research.
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