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

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

doi:10.1172/JCI88736

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

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

Biology

Research output: Contribution to journal › Article › peer-review

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 prometastatic 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.

Original language	English
Pages (from-to)	117-131
Number of pages	15
Journal	Journal of Clinical Investigation
Volume	127
Issue number	1
Early online date	21 Nov 2016
DOIs	https://doi.org/10.1172/JCI88736
Publication status	Published - 3 Jan 2017

Bibliographical note

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Keywords

Adenocarcinoma/genetics
Cell Line, Tumor
Cell Movement
Epithelial-Mesenchymal Transition
Gene Deletion
Golgi Apparatus/genetics
Humans
Lung Neoplasms/genetics
Membrane Proteins/genetics
MicroRNAs/genetics
Neoplasm Metastasis
Neoplasm Proteins/genetics
Protein Domains
RNA, Neoplasm/genetics
Receptors, Progesterone/genetics
Zinc Finger E-box-Binding Homeobox 1/genetics

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10.1172/JCI88736

JCI88736
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Tan, X., Banerjee, P., Guo, H.-F., Ireland, S., Pankova, D., Ahn, Y., Nikolaidis, I. M., Liu, X., Zhao, Y., Xue, Y., Burns, A. R., Roybal, J., Gibbons, D. L., Zal, T., Creighton, C. J., Ungar, D., Wang, Y., & Kurie, J. M. (2017). Epithelial-to-mesenchymal transition drives a pro-metastatic Golgi compaction process through scaffolding protein PAQR11. Journal of Clinical Investigation, 127(1), 117-131. https://doi.org/10.1172/JCI88736

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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 prometastatic 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.",

keywords = "Adenocarcinoma/genetics, Cell Line, Tumor, Cell Movement, Epithelial-Mesenchymal Transition, Gene Deletion, Golgi Apparatus/genetics, Humans, Lung Neoplasms/genetics, Membrane Proteins/genetics, MicroRNAs/genetics, Neoplasm Metastasis, Neoplasm Proteins/genetics, Protein Domains, RNA, Neoplasm/genetics, Receptors, Progesterone/genetics, Zinc Finger E-box-Binding Homeobox 1/genetics",

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

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Tan, X, Banerjee, P, Guo, H-F, Ireland, S, Pankova, D, Ahn, Y, Nikolaidis, IM, Liu, X, Zhao, Y, Xue, Y, Burns, AR, Roybal, J, Gibbons, DL, Zal, T, Creighton, CJ, Ungar, D, Wang, Y & Kurie, JM 2017, 'Epithelial-to-mesenchymal transition drives a pro-metastatic Golgi compaction process through scaffolding protein PAQR11', Journal of Clinical Investigation, vol. 127, no. 1, pp. 117-131. https://doi.org/10.1172/JCI88736

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T1 - Epithelial-to-mesenchymal transition drives a pro-metastatic Golgi compaction process through scaffolding protein PAQR11

AU - Tan, Xiaochao

AU - Banerjee, Priyam

AU - Guo, Hou-Fu

AU - Ireland, Stephen

AU - Pankova, Daniela

AU - Ahn, Young-ho

AU - Nikolaidis, Irodotos Michail

AU - Liu, Xin

AU - Zhao, Yanbin

AU - Xue, Yongming

AU - Burns, Alan R.

AU - Roybal, Jonathon

AU - Gibbons, Don L.

AU - Zal, Tomasz

AU - Creighton, Chad J.

AU - Ungar, Daniel

AU - Wang, Yanzhuang

AU - Kurie, Jonathan M.

N1 - Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details

PY - 2017/1/3

Y1 - 2017/1/3

N2 - 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 prometastatic 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.

AB - 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 prometastatic 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.

KW - Adenocarcinoma/genetics

KW - Cell Line, Tumor

KW - Cell Movement

KW - Epithelial-Mesenchymal Transition

KW - Gene Deletion

KW - Golgi Apparatus/genetics

KW - Humans

KW - Lung Neoplasms/genetics

KW - Membrane Proteins/genetics

KW - MicroRNAs/genetics

KW - Neoplasm Metastasis

KW - Neoplasm Proteins/genetics

KW - Protein Domains

KW - RNA, Neoplasm/genetics

KW - Receptors, Progesterone/genetics

KW - Zinc Finger E-box-Binding Homeobox 1/genetics

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U2 - 10.1172/JCI88736

DO - 10.1172/JCI88736

M3 - Article

SN - 0021-9738

VL - 127

SP - 117

EP - 131

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 1

ER -

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

Abstract

Bibliographical note

Keywords

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Dani Ungar

Modulation of glycosylation homeostasis by

Cite this

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

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Profiles

Dani Ungar

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Modulation of glycosylation homeostasis by

Cite this