Related Experiment Video

Updated: Oct 25, 2025

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

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AMBRA1 Promotes TGFβ Signaling via Nonproteolytic Polyubiquitylation of Smad4

Jinquan Liu1,2, Bo Yuan1,2, Jin Cao1,2

  • 1The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, P.R. China.

Cancer Research
|August 7, 2021
PubMed

Insights

AMBRA1 enhances transforming growth factor beta (TGFβ) signaling by increasing Smad4 polyubiquitylation. This promotes breast cancer cell migration and metastasis, identifying AMBRA1 as a potential therapeutic target.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Transforming growth factor beta (TGFβ) signaling is crucial in advanced cancers, primarily mediated by Smad proteins.
  • Smad4 is a key transducer in the TGFβ pathway, but its transcriptional regulation mechanisms are not fully elucidated.

Purpose of the Study:

  • To investigate the role of AMBRA1 in regulating Smad4 transcriptional activity and TGFβ signaling.
  • To determine AMBRA1's impact on breast cancer cell behavior and metastasis.

Main Methods:

  • Investigated the interaction between AMBRA1 and Smad4 within the CUL4-RING (CRL4) ubiquitin ligase complex.
  • Assessed the effect of CRL4-AMBRA1 on Smad4 polyubiquitylation and transcriptional activity.
  • Utilized breast cancer cell lines and mouse models to evaluate the functional consequences of AMBRA1 on metastasis.

Main Results:

  • AMBRA1 acts as a substrate receptor for Smad4 in the CRL4 ubiquitin ligase complex.
  • CRL4-AMBRA1 mediates nonproteolytic polyubiquitylation of Smad4, enhancing its transcriptional functions.
  • AMBRA1 significantly potentiates TGFβ signaling, promoting epithelial-to-mesenchymal transition, migration, invasion, and metastasis in breast cancer models.

Conclusions:

  • CRL4-AMBRA1 complex enhances Smad4 polyubiquitylation, thereby facilitating TGFβ-driven breast cancer metastasis.
  • AMBRA1 emerges as a novel regulator of TGFβ signaling and a potential therapeutic target for metastatic breast cancer.

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