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<p>The TGF-β signaling pathway is initiated when the type II receptor phosphorylates the type I receptor (ALK5) upon TGF-β binding. While E3 ubiquitin ligases regulate TGF-β receptor degradation, their role in modulating receptor catalytic activity via ubiquitination remains largely unexplored. Here, we demonstrate that the E3 ubiquitin ligase MARCH2 enhances ALK5 catalytic activity by conjugating K63-linked ubiquitin chains to lysines 342/343 (K342/343), primarily at endosomes following TGF-β-induced endocytosis. Mutations of ALK5 at K342/343 (K342/343R) abolish its catalytic activity for SMAD2 phosphorylation, leading to impaired TGF-β responses and reduced cell migration in A549 cells. In a mouse model, expression of the ALK5 K342/343 R mutant significantly decreases lung metastasis compared to wild-type ALK5. TCGA analysis further revealed a strong positive correlation between MARCH2 expression and TGF-β target gene expression. Collectively, these findings establish ALK5 ubiquitination at K342/343 by MARCH2 as a crucial regulatory mechanism for ALK5 catalytic activity, TGF-β signaling, and metastasis.</p>

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MARCH2-mediated Lys63-linked polyubiquitination promotes metastasis by modulating the catalytic activity of TGF-β type I receptor

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月10日

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  • Kun Tae,
  • Sang Woo Cho,
  • Seonjeong Lee,
  • Dahyoon Heo,
  • Hyo Sun Cha,
  • Da Yeon Lee,
  • Eunjeong Oh,
  • Minhyeong Choi,
  • Donghyuk Shin,
  • Siyoung Yang,
  • Cheolju Lee,
  • Cheol Yong Choi

摘要

The TGF-β signaling pathway is initiated when the type II receptor phosphorylates the type I receptor (ALK5) upon TGF-β binding. While E3 ubiquitin ligases regulate TGF-β receptor degradation, their role in modulating receptor catalytic activity via ubiquitination remains largely unexplored. Here, we demonstrate that the E3 ubiquitin ligase MARCH2 enhances ALK5 catalytic activity by conjugating K63-linked ubiquitin chains to lysines 342/343 (K342/343), primarily at endosomes following TGF-β-induced endocytosis. Mutations of ALK5 at K342/343 (K342/343R) abolish its catalytic activity for SMAD2 phosphorylation, leading to impaired TGF-β responses and reduced cell migration in A549 cells. In a mouse model, expression of the ALK5 K342/343 R mutant significantly decreases lung metastasis compared to wild-type ALK5. TCGA analysis further revealed a strong positive correlation between MARCH2 expression and TGF-β target gene expression. Collectively, these findings establish ALK5 ubiquitination at K342/343 by MARCH2 as a crucial regulatory mechanism for ALK5 catalytic activity, TGF-β signaling, and metastasis.