TY - JOUR
T1 - PKD1 Phosphorylation-Dependent Degradation of SNAIL by SCF-FBXO11 Regulates Epithelial-Mesenchymal Transition and Metastasis
AU - Zheng, Hanqiu
AU - Shen, Minhong
AU - Zha, Yin Lian
AU - Li, Wenyang
AU - Wei, Yong
AU - Blanco, Mario Andres
AU - Ren, Guangwen
AU - Zhou, Tianhua
AU - Storz, Peter
AU - Wang, Hui Yun
AU - Kang, Yibin
N1 - Funding Information:
We thank Dr. R.A. Weinberg for providing HMLEN cells and Dr. B.P. Zhou for providing the SNAIL-2SA, SNAIL-4SA, and SNAIL-6SA plasmids. We thank Dr. M. Pagano for providing FLAG-tagged FBXO11, FBXO1, FBXO5, FBXO10, FBXO31, FBXW1, and FBXW9 and for helpful advice. We thank B. Ell, M.B. Esposito, B.I. Koh, L. Wan, R. Chakrabarti, and other laboratory members for helpful discussions; M. Yuan for technical assistance; and C. DeCoste for assistance with flow cytometry. We thank L. Cong at the Tissue Analytic Service Core of Cancer Institute of New Jersey for optimizing the conditions for IHC staining of clinical tumor samples. This research was supported by a CINJ Research Development Award; by the Brewster Foundation; and by grants from the U.S. Department of Defense (BC123187), the NIH (R01CA134519 and R01CA141062 to Y.K. and GM086435 and CA140182 to P.S.) and the National Science Foundation of China (to Y.K. and H-Y.W.),. H.Z. is a recipient of a Komen for the Cure postdoctoral fellowship (KG111164), and G. R. is a recipient of a DOD postdoctoral fellowship (BC123284). M.S. is supported by the 111 Project of China (B13026, Department of Education) and by an international exchange program of Zhejiang University.
Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2014
Y1 - 2014
N2 - 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.
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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U2 - 10.1016/j.ccr.2014.07.022
DO - 10.1016/j.ccr.2014.07.022
M3 - Article
C2 - 25203322
AN - SCOPUS:84908666051
SN - 1535-6108
VL - 26
SP - 358
EP - 373
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -