Erbin interacts with NHERF1 and Ezrin to stabilize a membrane ErbB2 signaling complex in HER2-positive breast cancer
Abstract Approximately 20% of breast cancers overexpress ErbB2/HER2/Neu, a receptor tyrosine kinase. Our previous studies demonstrated that HER2 interacts with the calcium pump, PMCA2, and the scaffolding molecules, NHERF1 and Ezrin to stabilize HER2/HSP90 interactions and contribute to the retentio...
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BMC
2025-05-01
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| Series: | Breast Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13058-025-02025-6 |
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| author | Jaekwang Jeong Kwangmin Yoo Jongwon Lee Jae Hun Shin Jungmin Choi John Wysolmerski |
| author_facet | Jaekwang Jeong Kwangmin Yoo Jongwon Lee Jae Hun Shin Jungmin Choi John Wysolmerski |
| author_sort | Jaekwang Jeong |
| collection | DOAJ |
| description | Abstract Approximately 20% of breast cancers overexpress ErbB2/HER2/Neu, a receptor tyrosine kinase. Our previous studies demonstrated that HER2 interacts with the calcium pump, PMCA2, and the scaffolding molecules, NHERF1 and Ezrin to stabilize HER2/HSP90 interactions and contribute to the retention of active HER2 at the plasma membrane. In the normal mammary epithelium where apical/basal polarity is tightly regulated by junctional proteins, HER2 is expressed at low levels in the basolateral membrane and interacts with the LAP family member, Erbin, whereas PMCA2, NHERF1, and Ezrin localize to the apical membrane. Here, we show that loss of apical membrane polarity in hyperplastic lesions of MMTV-Neu mammary glands or in human DCIS leads to intermixing of these molecules and allows Erbin to interact with NHERF1, Ezrin and HER2 initially within the basolateral membrane and then more diffusely throughout the plasma membrane. In SKBR3 cells, Erbin interacts with NHERF1, Ezrin and HER2 in actin-rich membrane protrusions that we have previously described to be sites of active HER2 signaling. Knockdown of Erbin in these cells reduced HER2 signaling by disrupting the formation of a HER2/NHERF1/Ezrin/HSP90 protein complex in the membrane protrusions. Furthermore, inhibition of Ezrin or knock-down of NHERF1 expression disrupted the ability of Erbin to interact with HER2. Taken together, our data suggest that Erbin supports HER2 stability, HER2 membrane retention and HER2 transforming ability by interacting with Ezrin and NHERF1 to maintain a multi-protein signaling complex necessary for HER2-mediated transformation. |
| format | Article |
| id | doaj-art-57de43d4ca3a4b7499f5aeafb46cf89f |
| institution | OA Journals |
| issn | 1465-542X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj-art-57de43d4ca3a4b7499f5aeafb46cf89f2025-08-20T02:29:51ZengBMCBreast Cancer Research1465-542X2025-05-0127111610.1186/s13058-025-02025-6Erbin interacts with NHERF1 and Ezrin to stabilize a membrane ErbB2 signaling complex in HER2-positive breast cancerJaekwang Jeong0Kwangmin Yoo1Jongwon Lee2Jae Hun Shin3Jungmin Choi4John Wysolmerski5Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of MedicineDepartment of Biomedical Sciences, Korea University College of MedicineDepartment of Biomedical Sciences, Korea University College of MedicineIntegrative Science and Engineering Division, Underwood International College, Yonsei UniversityDepartment of Biomedical Sciences, Korea University College of MedicineSection of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of MedicineAbstract Approximately 20% of breast cancers overexpress ErbB2/HER2/Neu, a receptor tyrosine kinase. Our previous studies demonstrated that HER2 interacts with the calcium pump, PMCA2, and the scaffolding molecules, NHERF1 and Ezrin to stabilize HER2/HSP90 interactions and contribute to the retention of active HER2 at the plasma membrane. In the normal mammary epithelium where apical/basal polarity is tightly regulated by junctional proteins, HER2 is expressed at low levels in the basolateral membrane and interacts with the LAP family member, Erbin, whereas PMCA2, NHERF1, and Ezrin localize to the apical membrane. Here, we show that loss of apical membrane polarity in hyperplastic lesions of MMTV-Neu mammary glands or in human DCIS leads to intermixing of these molecules and allows Erbin to interact with NHERF1, Ezrin and HER2 initially within the basolateral membrane and then more diffusely throughout the plasma membrane. In SKBR3 cells, Erbin interacts with NHERF1, Ezrin and HER2 in actin-rich membrane protrusions that we have previously described to be sites of active HER2 signaling. Knockdown of Erbin in these cells reduced HER2 signaling by disrupting the formation of a HER2/NHERF1/Ezrin/HSP90 protein complex in the membrane protrusions. Furthermore, inhibition of Ezrin or knock-down of NHERF1 expression disrupted the ability of Erbin to interact with HER2. Taken together, our data suggest that Erbin supports HER2 stability, HER2 membrane retention and HER2 transforming ability by interacting with Ezrin and NHERF1 to maintain a multi-protein signaling complex necessary for HER2-mediated transformation.https://doi.org/10.1186/s13058-025-02025-6ErbinHER2NHERF1EzrinApical/basal polarityHSP90 |
| spellingShingle | Jaekwang Jeong Kwangmin Yoo Jongwon Lee Jae Hun Shin Jungmin Choi John Wysolmerski Erbin interacts with NHERF1 and Ezrin to stabilize a membrane ErbB2 signaling complex in HER2-positive breast cancer Breast Cancer Research Erbin HER2 NHERF1 Ezrin Apical/basal polarity HSP90 |
| title | Erbin interacts with NHERF1 and Ezrin to stabilize a membrane ErbB2 signaling complex in HER2-positive breast cancer |
| title_full | Erbin interacts with NHERF1 and Ezrin to stabilize a membrane ErbB2 signaling complex in HER2-positive breast cancer |
| title_fullStr | Erbin interacts with NHERF1 and Ezrin to stabilize a membrane ErbB2 signaling complex in HER2-positive breast cancer |
| title_full_unstemmed | Erbin interacts with NHERF1 and Ezrin to stabilize a membrane ErbB2 signaling complex in HER2-positive breast cancer |
| title_short | Erbin interacts with NHERF1 and Ezrin to stabilize a membrane ErbB2 signaling complex in HER2-positive breast cancer |
| title_sort | erbin interacts with nherf1 and ezrin to stabilize a membrane erbb2 signaling complex in her2 positive breast cancer |
| topic | Erbin HER2 NHERF1 Ezrin Apical/basal polarity HSP90 |
| url | https://doi.org/10.1186/s13058-025-02025-6 |
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