MAL2 mediates the formation of stable HER2 signaling complexes within lipid raft-rich membrane protrusions in breast cancer cells

Jaekwang Jeong; Jae Hun Shin; Wenxue Li; Jun Young Hong; Jaechul Lim; Jae Yeon Hwang; Jean Ju Chung; Qin Yan; Yansheng Liu; Jungmin Choi; John Wysolmerski

doi:10.1016/j.celrep.2021.110160

MAL2 mediates the formation of stable HER2 signaling complexes within lipid raft-rich membrane protrusions in breast cancer cells

Jaekwang Jeong, Jae Hun Shin, Wenxue Li, Jun Young Hong, Jaechul Lim, Jae Yeon Hwang, Jean Ju Chung, Qin Yan, Yansheng Liu, Jungmin Choi, John Wysolmerski

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

7 Citations (Scopus)

Abstract

The lipid raft-resident protein, MAL2, has been implicated as contributing to the pathogenesis of several malignancies, including breast cancer, but the underlying mechanism for its effects on tumorigenesis is unknown. Here, we show that MAL2-mediated lipid raft formation leads to HER2 plasma membrane retention and enhanced HER2 signaling in breast cancer cells. We demonstrate physical interactions between HER2 and MAL2 in lipid rafts using proximity ligation assays. Super-resolution structured illumination microscopy imaging displays the structural organization of the HER2/Ezrin/NHERF1/PMCA2 protein complex. Formation of this protein complex maintains low intracellular calcium concentrations in the vicinity of the plasma membrane. HER2/MAL2 protein interactions in lipid rafts are enhanced in trastuzumab-resistant breast cancer cells. Our findings suggest that MAL2 is crucial for lipid raft formation, HER2 signaling, and HER2 membrane stability in breast cancer cells, suggesting MAL2 as a potential therapeutic target.

Original language	English
Article number	110160
Journal	Cell Reports
Volume	37
Issue number	13
DOIs	https://doi.org/10.1016/j.celrep.2021.110160
Publication status	Published - 2021 Dec 28

Bibliographical note

Funding Information:
This work was supported by Departmental Supplement for imaging system and NIH grant R01 HD096745 to J.J.C. a Male Contraceptive Initiative (MCI) post-doctoral fellow to J.Y.H. NIH grant R01 CA237586 to Q.Y. NRF of Korea (NRF-2019R1A4A1029000) to J.C. and NIH grants R01 HD100468 and R01 HD076248 to J.W. J.J. designed and conducted the experiments, analyzed the data, and wrote the manuscript. J.S. analyzed the data and wrote the manuscript. W.L. and Y.L. performed and analyzed mass spectrometry measurements. J.Y.H. and J.L. performed ATAC-seq. J.Y.H. and J.J.C. helped with 3D super-resolution SIM imaging. Q.Y. provided trastuzumab-resistant breast cancer cell lines. J.C. analyzed scRNA-seq, ATAC-seq, and microarray data. J.W. wrote the manuscript. The authors declare no competing interests.

Funding Information:
This work was supported by Departmental Supplement for imaging system and NIH grant R01 HD096745 to J.J.C., a Male Contraceptive Initiative ( MCI ) post-doctoral fellow to J.Y.H., NIH grant R01 CA237586 to Q.Y., NRF of Korea ( NRF-2019R1A4A1029000 ) to J.C., and NIH grants R01 HD100468 and R01 HD076248 to J.W.

Publisher Copyright:
© 2021 The Authors

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2021.110160

Cite this

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title = "MAL2 mediates the formation of stable HER2 signaling complexes within lipid raft-rich membrane protrusions in breast cancer cells",

abstract = "The lipid raft-resident protein, MAL2, has been implicated as contributing to the pathogenesis of several malignancies, including breast cancer, but the underlying mechanism for its effects on tumorigenesis is unknown. Here, we show that MAL2-mediated lipid raft formation leads to HER2 plasma membrane retention and enhanced HER2 signaling in breast cancer cells. We demonstrate physical interactions between HER2 and MAL2 in lipid rafts using proximity ligation assays. Super-resolution structured illumination microscopy imaging displays the structural organization of the HER2/Ezrin/NHERF1/PMCA2 protein complex. Formation of this protein complex maintains low intracellular calcium concentrations in the vicinity of the plasma membrane. HER2/MAL2 protein interactions in lipid rafts are enhanced in trastuzumab-resistant breast cancer cells. Our findings suggest that MAL2 is crucial for lipid raft formation, HER2 signaling, and HER2 membrane stability in breast cancer cells, suggesting MAL2 as a potential therapeutic target.",

author = "Jaekwang Jeong and Shin, {Jae Hun} and Wenxue Li and Hong, {Jun Young} and Jaechul Lim and Hwang, {Jae Yeon} and Chung, {Jean Ju} and Qin Yan and Yansheng Liu and Jungmin Choi and John Wysolmerski",

note = "Funding Information: This work was supported by Departmental Supplement for imaging system and NIH grant R01 HD096745 to J.J.C. a Male Contraceptive Initiative (MCI) post-doctoral fellow to J.Y.H. NIH grant R01 CA237586 to Q.Y. NRF of Korea (NRF-2019R1A4A1029000) to J.C. and NIH grants R01 HD100468 and R01 HD076248 to J.W. J.J. designed and conducted the experiments, analyzed the data, and wrote the manuscript. J.S. analyzed the data and wrote the manuscript. W.L. and Y.L. performed and analyzed mass spectrometry measurements. J.Y.H. and J.L. performed ATAC-seq. J.Y.H. and J.J.C. helped with 3D super-resolution SIM imaging. Q.Y. provided trastuzumab-resistant breast cancer cell lines. J.C. analyzed scRNA-seq, ATAC-seq, and microarray data. J.W. wrote the manuscript. The authors declare no competing interests. Funding Information: This work was supported by Departmental Supplement for imaging system and NIH grant R01 HD096745 to J.J.C., a Male Contraceptive Initiative ( MCI ) post-doctoral fellow to J.Y.H., NIH grant R01 CA237586 to Q.Y., NRF of Korea ( NRF-2019R1A4A1029000 ) to J.C., and NIH grants R01 HD100468 and R01 HD076248 to J.W. Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = dec,

day = "28",

doi = "10.1016/j.celrep.2021.110160",

language = "English",

volume = "37",

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T1 - MAL2 mediates the formation of stable HER2 signaling complexes within lipid raft-rich membrane protrusions in breast cancer cells

AU - Jeong, Jaekwang

AU - Shin, Jae Hun

AU - Li, Wenxue

AU - Hong, Jun Young

AU - Lim, Jaechul

AU - Hwang, Jae Yeon

AU - Chung, Jean Ju

AU - Yan, Qin

AU - Liu, Yansheng

AU - Choi, Jungmin

AU - Wysolmerski, John

N1 - Funding Information: This work was supported by Departmental Supplement for imaging system and NIH grant R01 HD096745 to J.J.C. a Male Contraceptive Initiative (MCI) post-doctoral fellow to J.Y.H. NIH grant R01 CA237586 to Q.Y. NRF of Korea (NRF-2019R1A4A1029000) to J.C. and NIH grants R01 HD100468 and R01 HD076248 to J.W. J.J. designed and conducted the experiments, analyzed the data, and wrote the manuscript. J.S. analyzed the data and wrote the manuscript. W.L. and Y.L. performed and analyzed mass spectrometry measurements. J.Y.H. and J.L. performed ATAC-seq. J.Y.H. and J.J.C. helped with 3D super-resolution SIM imaging. Q.Y. provided trastuzumab-resistant breast cancer cell lines. J.C. analyzed scRNA-seq, ATAC-seq, and microarray data. J.W. wrote the manuscript. The authors declare no competing interests. Funding Information: This work was supported by Departmental Supplement for imaging system and NIH grant R01 HD096745 to J.J.C., a Male Contraceptive Initiative ( MCI ) post-doctoral fellow to J.Y.H., NIH grant R01 CA237586 to Q.Y., NRF of Korea ( NRF-2019R1A4A1029000 ) to J.C., and NIH grants R01 HD100468 and R01 HD076248 to J.W. Publisher Copyright: © 2021 The Authors

PY - 2021/12/28

Y1 - 2021/12/28

N2 - The lipid raft-resident protein, MAL2, has been implicated as contributing to the pathogenesis of several malignancies, including breast cancer, but the underlying mechanism for its effects on tumorigenesis is unknown. Here, we show that MAL2-mediated lipid raft formation leads to HER2 plasma membrane retention and enhanced HER2 signaling in breast cancer cells. We demonstrate physical interactions between HER2 and MAL2 in lipid rafts using proximity ligation assays. Super-resolution structured illumination microscopy imaging displays the structural organization of the HER2/Ezrin/NHERF1/PMCA2 protein complex. Formation of this protein complex maintains low intracellular calcium concentrations in the vicinity of the plasma membrane. HER2/MAL2 protein interactions in lipid rafts are enhanced in trastuzumab-resistant breast cancer cells. Our findings suggest that MAL2 is crucial for lipid raft formation, HER2 signaling, and HER2 membrane stability in breast cancer cells, suggesting MAL2 as a potential therapeutic target.

AB - The lipid raft-resident protein, MAL2, has been implicated as contributing to the pathogenesis of several malignancies, including breast cancer, but the underlying mechanism for its effects on tumorigenesis is unknown. Here, we show that MAL2-mediated lipid raft formation leads to HER2 plasma membrane retention and enhanced HER2 signaling in breast cancer cells. We demonstrate physical interactions between HER2 and MAL2 in lipid rafts using proximity ligation assays. Super-resolution structured illumination microscopy imaging displays the structural organization of the HER2/Ezrin/NHERF1/PMCA2 protein complex. Formation of this protein complex maintains low intracellular calcium concentrations in the vicinity of the plasma membrane. HER2/MAL2 protein interactions in lipid rafts are enhanced in trastuzumab-resistant breast cancer cells. Our findings suggest that MAL2 is crucial for lipid raft formation, HER2 signaling, and HER2 membrane stability in breast cancer cells, suggesting MAL2 as a potential therapeutic target.

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DO - 10.1016/j.celrep.2021.110160

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AN - SCOPUS:85121687335

SN - 2211-1247

VL - 37

JO - Cell Reports

JF - Cell Reports

IS - 13

M1 - 110160

ER -

MAL2 mediates the formation of stable HER2 signaling complexes within lipid raft-rich membrane protrusions in breast cancer cells

Abstract

Bibliographical note

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UN SDGs

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