AMBRA1 Promotes TGFß Signaling via Nonproteolytic Polyubiquitylation of Smad4.
Cancer Res
; 81(19): 5007-5020, 2021 10 01.
Article
in En
| MEDLINE
| ID: mdl-34362797
ABSTRACT
Transforming growth factor ß (TGFß) 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 TGFß 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 TGFß signaling and critically promoted TGFß-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 TGFß-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 TGFß signaling and breast cancer metastasis, supporting further exploration of AMBRA1 as a target for cancer therapy.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Signal Transduction
/
Transforming Growth Factor beta
/
Adaptor Proteins, Signal Transducing
/
Smad4 Protein
Type of study:
Etiology_studies
/
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Cancer Res
Year:
2021
Document type:
Article