Epithelial-to-mesenchymal transition drives a pro-metastatic Golgi compaction process through scaffolding protein PAQR11
Xiaochao Tan, … , Yanzhuang Wang, Jonathan M. Kurie
Xiaochao Tan, … , Yanzhuang Wang, Jonathan M. Kurie
Published November 21, 2016
Citation Information: J Clin Invest. 2017;127(1):117-131. https://doi.org/10.1172/JCI88736.
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Research Article Cell biology Oncology

Epithelial-to-mesenchymal transition drives a pro-metastatic Golgi compaction process through scaffolding protein PAQR11

Abstract

Tumor cells gain metastatic capacity through a Golgi phosphoprotein 3–dependent (GOLPH3-dependent) Golgi membrane dispersal process that drives the budding and transport of secretory vesicles. Whether Golgi dispersal underlies the pro-metastatic vesicular trafficking that is associated with epithelial-to-mesenchymal transition (EMT) remains unclear. Here, we have shown that, rather than causing Golgi dispersal, EMT led to the formation of compact Golgi organelles with improved ribbon linking and cisternal stacking. Ectopic expression of the EMT-activating transcription factor ZEB1 stimulated Golgi compaction and relieved microRNA-mediated repression of the Golgi scaffolding protein PAQR11. Depletion of PAQR11 dispersed Golgi organelles and impaired anterograde vesicle transport to the plasma membrane as well as retrograde vesicle tethering to the Golgi. The N-terminal scaffolding domain of PAQR11 was associated with key regulators of Golgi compaction and vesicle transport in pull-down assays and was required to reconstitute Golgi compaction in PAQR11-deficient tumor cells. Finally, high PAQR11 levels were correlated with EMT and shorter survival in human cancers, and PAQR11 was found to be essential for tumor cell migration and metastasis in EMT-driven lung adenocarcinoma models. We conclude that EMT initiates a PAQR11-mediated Golgi compaction process that drives metastasis.

Authors

Xiaochao Tan, Priyam Banerjee, Hou-Fu Guo, Stephen Ireland, Daniela Pankova, Young-ho Ahn, Irodotos Michail Nikolaidis, Xin Liu, Yanbin Zhao, Yongming Xue, Alan R. Burns, Jonathon Roybal, Don L. Gibbons, Tomasz Zal, Chad J. Creighton, Daniel Ungar, Yanzhuang Wang, Jonathan M. Kurie

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Figure 5

PAQR11 has scaffolding functions required for Golgi compaction.

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PAQR11 has scaffolding functions required for Golgi compaction. (A) PAQR...
(A) PAQR11-associated proteins identified by liquid chromatography–tandem mass spectrometry. Lines indicate known protein-protein interactions as shown here by pull-down assays (present study) and as reported in Biological General Repository for Interaction Data sets (BioGRID), Biomolecular Interaction Network Database (BIND), and Human Protein Reference Database (HPRD). (B) Scatter plots show the average Golgi element number (left) and areas (right) in 344SQ_shPAQR11 cells stably transfected with vectors that express EGFP alone (shPAQR11_EGFP), WT PAQR11 (shPAQR11_EGFP-PAQR11), or mutant PAQR11 that lacks amino acids 1–5 (shPAQR11_EGFP-PAQR11ΔN5). Each dot represents values from a single cell. (C) The scatter plot shows Golgi areas normalized to nuclear areas in 344SQ_shPAQR11 cells stably transfected with vectors that express EGFP alone (shPAQR11_EGFP), WT PAQR11 (shPAQR11_EGFP-PAQR11), or mutant PAQR11 that lacks amino acids 1–5 (shPAQR11_EGFP-PAQR11ΔN5). Each dot represents values from a single cell. P values were determined using 2-tailed Student’s t test or ANOVA for comparisons between 2 groups or more than 2 groups, respectively. Results in B and C were replicated (n ≥ 2 experiments).