PKD1 Phosphorylation-Dependent Degradation of SNAIL by SCF-FBXO11 Regulates Epithelial-Mesenchymal Transition and Metastasis

Hanqiu Zheng, Minhong Shen, Yin Lian Zha, Wenyang Li, Yong Wei, Mario Andres Blanco, Guangwen Ren, Tianhua Zhou, Peter Storz, Hui Yun Wang, Yibin Kang

Research output: Contribution to journalArticle

121 Scopus citations

Abstract

Metastatic dissemination is often initiated by the reactivation of an embryonic development program referred to as epithelial-mesenchymal transition (EMT). The transcription factor SNAIL promotes EMT and elicits associated pathological characteristics such as invasion, metastasis, and stemness. To better understand the posttranslational regulation of SNAIL, we performed a luciferase-based, genome-wide E3 ligase siRNA library screen and identified SCF-FBXO11 as an important E3 that targets SNAIL for ubiquitylation and degradation. Furthermore, we discovered that SNAIL degradation by FBXO11 is dependent on Ser-11 phosphorylation of SNAIL by protein kinase D1 (PKD1). FBXO11 blocks SNAIL-induced EMT, tumor initiation, and metastasis in multiple breast cancer models. These findings establish the PKD1-FBXO11-SNAIL axis as a mechanism of posttranslational regulation of EMT and cancer metastasis.

Original languageEnglish (US)
Pages (from-to)358-373
Number of pages16
JournalCancer cell
Volume26
Issue number3
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Zheng, H., Shen, M., Zha, Y. L., Li, W., Wei, Y., Blanco, M. A., Ren, G., Zhou, T., Storz, P., Wang, H. Y., & Kang, Y. (2014). PKD1 Phosphorylation-Dependent Degradation of SNAIL by SCF-FBXO11 Regulates Epithelial-Mesenchymal Transition and Metastasis. Cancer cell, 26(3), 358-373. https://doi.org/10.1016/j.ccr.2014.07.022