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.
Bibliographical noteFunding 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.
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.
© 2021 The Authors
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)