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

• Published in: Cell reports (Cambridge) 2021-12, Vol.37 (13), p.110160-110160, Article 110160
• Main Authors: Jeong, Jaekwang, Shin, Jae Hun, Li, Wenxue, Hong, Jun Young, Lim, Jaechul, Hwang, Jae Yeon, Chung, Jean-Ju, Yan, Qin, Liu, Yansheng, Choi, Jungmin, Wysolmerski, John
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Immunological - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Proliferation; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Drug Resistance, Neoplasm; Endocytosis; Female; HER2; Humans; lipid rafts; MAL2; Membrane Microdomains - drug effects; Membrane Microdomains - metabolism; membrane protrusions; Myelin and Lymphocyte-Associated Proteolipid Proteins - genetics; Myelin and Lymphocyte-Associated Proteolipid Proteins - metabolism; Phosphoproteins - genetics; Phosphoproteins - metabolism; Plasma Membrane Calcium-Transporting ATPases - genetics; Plasma Membrane Calcium-Transporting ATPases - metabolism; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Sodium-Hydrogen Exchangers - genetics; Sodium-Hydrogen Exchangers - metabolism; Trastuzumab - pharmacology; Tumor Cells, Cultured
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.110160

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. [Display omitted] •MAL2 is required for HER2 membrane retention and signaling in breast cancer cells•MAL2 strengthens the formation of the HER2/Ezrin/NHERF1/PMCA2 protein complex•Loss of MAL2 increases plasma membrane calcium concentration•HER2/MAL2 interaction is enhanced in trastuzumab-resistant breast cancer cells Jeong et al. show that the formation of MAL2-mediated lipid raft-rich membrane protrusions is crucial for HER2 signaling in breast cancer cells. MAL2 is required for the formation of HER2/Ezrin/NHERF1/PMCA2 protein complexes. Formation of these protein complexes leads to a low calcium environment in the plasma membrane