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, MarioAndres Blanco, Guangwen Ren, Tianhua Zhou, Peter Storz, Hui Yun Wang, Yibin Kang

Research output: Contribution to journalArticle

108 Citations (Scopus)

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 - 2014

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Epithelial-Mesenchymal Transition
Protein Kinases
Phosphorylation
Neoplasm Metastasis
Ubiquitin-Protein Ligases
Ubiquitination
Luciferases
Small Interfering RNA
Embryonic Development
Neoplasms
Transcription Factors
Genome
Breast Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

PKD1 Phosphorylation-Dependent Degradation of SNAIL by SCF-FBXO11 Regulates Epithelial-Mesenchymal Transition and Metastasis. / Zheng, Hanqiu; Shen, Minhong; Zha, Yin Lian; Li, Wenyang; Wei, Yong; Blanco, MarioAndres; Ren, Guangwen; Zhou, Tianhua; Storz, Peter; Wang, Hui Yun; Kang, Yibin.

In: Cancer Cell, Vol. 26, No. 3, 2014, p. 358-373.

Research output: Contribution to journalArticle

Zheng, H, Shen, M, Zha, YL, Li, W, Wei, Y, Blanco, M, Ren, G, Zhou, T, Storz, P, Wang, HY & Kang, Y 2014, 'PKD1 Phosphorylation-Dependent Degradation of SNAIL by SCF-FBXO11 Regulates Epithelial-Mesenchymal Transition and Metastasis', Cancer Cell, vol. 26, no. 3, pp. 358-373. https://doi.org/10.1016/j.ccr.2014.07.022
Zheng, Hanqiu ; Shen, Minhong ; Zha, Yin Lian ; Li, Wenyang ; Wei, Yong ; Blanco, MarioAndres ; Ren, Guangwen ; Zhou, Tianhua ; Storz, Peter ; Wang, Hui Yun ; Kang, Yibin. / PKD1 Phosphorylation-Dependent Degradation of SNAIL by SCF-FBXO11 Regulates Epithelial-Mesenchymal Transition and Metastasis. In: Cancer Cell. 2014 ; Vol. 26, No. 3. pp. 358-373.
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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.",
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AU - Zha, Yin Lian

AU - Li, Wenyang

AU - Wei, Yong

AU - Blanco, MarioAndres

AU - Ren, Guangwen

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AB - 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.

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