American Association for Cancer Research
00085472can210431-sup-260401_2_supp_7279834_qwqpm9.pdf (135.52 kB)

Supplementary Figure S3 from AMBRA1 Promotes TGFβ Signaling via Nonproteolytic Polyubiquitylation of Smad4

Download (135.52 kB)
journal contribution
posted on 2023-03-31, 04:26 authored by Jinquan Liu, Bo Yuan, Jin Cao, Hongjie Luo, Shuchen Gu, Mengdi Zhang, Ran Ding, Long Zhang, Fangfang Zhou, Mien-Chie Hung, Pinglong Xu, Xia Lin, Jianping Jin, Xin-Hua Feng

CRL4-AMBRA1 promotes Smad4 poly-ubiquitylation via the K63 linkage.


National Natural Science Foundation of China

Fundamental Research Funds for the Central Universities



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. 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.

Usage metrics

    Cancer Research



    Ref. manager