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 journalArticlepeer-review

4 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 languageEnglish
Article number110160
JournalCell Reports
Volume37
Issue number13
DOIs
Publication statusPublished - 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)

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