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

Department of Molecular Medicine

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

77 Scopus citations

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
DOIs	https://doi.org/10.1172/JCI88736
State	Published - 3 Jan 2017

Bibliographical note

Funding Information:
We thank Yiqun Zhang, Bih-Fang Pan, and Xiaoyan Zhang for technical assistance. This work was supported by the NIH through R01 CA181184 (to JMK), R01 CA125123 (to CJC), GM087364 (to YW), GM105920 (to YW), GM112786P30 (to YW), EY007551 (to ARB), K08 CA151661 (to DLG), NRF-2010-0027945 (to YHA), and MD Anderson Cancer Center Support Grant CA016672; by the American Cancer Society through RGS-09-278-01-CSM (to YW); by Cancer Prevention Research Institute of Texas (CPRIT) Multi-investigator Research Award RP120713 (to JMK, CJC, and DLG); and by MCubed and the Fastforward Protein Folding Disease Initiative of the University of Michigan (to YW). JMK holds the Elza A. and Ina S. Freeman Endowed Professorship in Lung Cancer. DLG is an R. Lee Clark Fellow of The University of Texas MD Anderson Cancer Center supported by the Jeane F. Shelby Scholarship Fund. MD Anderson's Proteomics and Metabolomics Facility is supported by MD Anderson Cancer Center, NIH High-End Instrumentation Program grant 1S10OD012304-0

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Tan, X., Banerjee, P., Guo, H. F., Ireland, S., Pankova, D., Ahn, Y. H., 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

@article{ee15f1a86ea44811bd22dd1362bd4705,

title = "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 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.",

author = "Xiaochao Tan and Priyam Banerjee and Guo, {Hou Fu} and Stephen Ireland and Daniela Pankova and Ahn, {Young Ho} 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.}",

note = "Funding Information: We thank Yiqun Zhang, Bih-Fang Pan, and Xiaoyan Zhang for technical assistance. This work was supported by the NIH through R01 CA181184 (to JMK), R01 CA125123 (to CJC), GM087364 (to YW), GM105920 (to YW), GM112786P30 (to YW), EY007551 (to ARB), K08 CA151661 (to DLG), NRF-2010-0027945 (to YHA), and MD Anderson Cancer Center Support Grant CA016672; by the American Cancer Society through RGS-09-278-01-CSM (to YW); by Cancer Prevention Research Institute of Texas (CPRIT) Multi-investigator Research Award RP120713 (to JMK, CJC, and DLG); and by MCubed and the Fastforward Protein Folding Disease Initiative of the University of Michigan (to YW). JMK holds the Elza A. and Ina S. Freeman Endowed Professorship in Lung Cancer. DLG is an R. Lee Clark Fellow of The University of Texas MD Anderson Cancer Center supported by the Jeane F. Shelby Scholarship Fund. MD Anderson's Proteomics and Metabolomics Facility is supported by MD Anderson Cancer Center, NIH High-End Instrumentation Program grant 1S10OD012304-0",

year = "2017",

month = jan,

day = "3",

doi = "10.1172/JCI88736",

language = "English",

volume = "127",

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journal = "Journal of Clinical Investigation",

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Tan, X, Banerjee, P, Guo, HF, Ireland, S, Pankova, D, Ahn, YH, 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

TY - JOUR

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 - Funding Information: We thank Yiqun Zhang, Bih-Fang Pan, and Xiaoyan Zhang for technical assistance. This work was supported by the NIH through R01 CA181184 (to JMK), R01 CA125123 (to CJC), GM087364 (to YW), GM105920 (to YW), GM112786P30 (to YW), EY007551 (to ARB), K08 CA151661 (to DLG), NRF-2010-0027945 (to YHA), and MD Anderson Cancer Center Support Grant CA016672; by the American Cancer Society through RGS-09-278-01-CSM (to YW); by Cancer Prevention Research Institute of Texas (CPRIT) Multi-investigator Research Award RP120713 (to JMK, CJC, and DLG); and by MCubed and the Fastforward Protein Folding Disease Initiative of the University of Michigan (to YW). JMK holds the Elza A. and Ina S. Freeman Endowed Professorship in Lung Cancer. DLG is an R. Lee Clark Fellow of The University of Texas MD Anderson Cancer Center supported by the Jeane F. Shelby Scholarship Fund. MD Anderson's Proteomics and Metabolomics Facility is supported by MD Anderson Cancer Center, NIH High-End Instrumentation Program grant 1S10OD012304-0

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.

UR - http://www.scopus.com/inward/record.url?scp=85008415074&partnerID=8YFLogxK

U2 - 10.1172/JCI88736

DO - 10.1172/JCI88736

M3 - Article

C2 - 27869652

AN - SCOPUS:85008415074

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

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