신재훈 (Yale University School of Medicine)

한빛사논문

조회699

Yale University School of Medicine

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Cell Reports, Volume 37, Issue 13, 28 December 2021, 110160 | https://doi.org/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^1,8,9,*, Jae Hun Shin^1,2,8, Wenxue Li³, Jun Young Hong⁴, Jaechul Lim², Jae Yeon Hwang⁵, Jean-Ju Chung⁵, Qin Yan⁶, Yansheng Liu³, Jungmin Choi⁷, John Wysolmerski¹

¹Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
²Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
³Department of Pharmacology, Cancer Biology Institute, Yale University School of Medicine, West Haven, CT 06516, USA
⁴Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
⁵Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA
⁶Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA
⁷Department of Biomedical Sciences, Korea University College of Medicine, Seoul, South Korea
⁸These authors contributed equally
⁹Lead contact

^*Corresponding author

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.

Keywords : MAL2, HER2, lipid rafts, membrane protrusions

논문정보

형식Research article
게재일2021년 12월 (BRIC 등록일 2022-02-07)
연구진국내+국외 연구진
분야 생명과학 > 세포생물학

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