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HER2 signaling regulates HER2 localization and membrane retention
Jaekwang Jeong1, Wonnam Kim1, Lark Kyun Kim2
1Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Plos One
|April 4, 2017
Summary
Human epidermal growth factor receptor 2 (HER2) signaling maintains cell surface protrusions, preventing its own degradation. This HER2 signaling is crucial for sustained signaling in breast cancer.
Area of Science:
- Oncology
- Cell Biology
- Molecular Signaling
Background:
- Human epidermal growth factor receptor 2 (HER2/Neu) is overexpressed in 25-30% of breast cancers.
- HER2 lacks known ligands but heterodimerizes with EGFR and ErbB3/HER3, crucial for breast cancer progression.
- Unlike other ErbB members, HER2 resists internalization and degradation, prolonging cell surface signaling.
Purpose of the Study:
- To investigate the role of HER2 signaling in maintaining its cell surface presence.
- To elucidate the mechanisms by which HER2 avoids internalization and degradation.
- To understand how HER2 signaling influences membrane protrusions and protein interactions.
Main Methods:
- Partial genetic knockdown of HER2 expression.
- Pharmacologic inhibition of HER2 signaling.
- Analysis of membrane protrusions, protein interactions (HER2, HSP90), ubiquitination, and internalization.
Main Results:
- HER2 signaling is essential for forming and maintaining membrane protrusions.
- HER2 signaling maintains PMCA2 expression and prevents elevated intracellular calcium.
- HER2 knockdown or inhibition disrupts protrusions, HSP90 interaction, leading to HER2 ubiquitination, internalization, and degradation.
Conclusions:
- A threshold of HER2 signaling is required to maintain signaling complexes.
- These complexes inhibit HER2 ubiquitination and internalization, prolonging signaling.
- This mechanism is vital for sustained HER2/EGFR or HER2/HER3 signaling in breast cancer.