title: PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates epithelial-mesenchymal transition and metastasis.
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.
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Hanqiu
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA; Department of Cell Biology and Program of Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Minhong
authors.initials: M
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Yin-Lian
authors.initials: YL
authors.lastname: Zha
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Wenyang
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Cell Biology, Harvard Medical School and Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Mario Andres
authors.initials: MA
authors.lastname: Blanco
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Guangwen
authors.initials: G
authors.lastname: Ren
authors.affiliation: Department of Cell Biology and Program of Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Tianhua
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Griffin Building, Room 306, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Storz
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Hui-Yun
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA; Genomic Instability and Tumor Progression Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA. Electronic address: ykang@princeton.edu.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Kang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition; D044783:F-Box Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D059748:Proteolysis; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D050396:TRPP Cation Channels / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D044783:F-Box Proteins; D011484:Protein-Arginine N-Methyltransferases; D044843:SKP Cullin F-Box Protein Ligases; D000071250:Snail Family Transcription Factors; D050396:TRPP Cation Channels; D014157:Transcription Factors; C457579:FBXO11 protein, human