The Scaffolding protein NHERF1 Regulates the Stability and Activity of the Tyrosine Kinase HER2 [Cell Biology]

Unlike other ErbB family members, ErbB2/HER2/Neu (HER2) is not internalized but remains on the cell surface when activated. This allows for prolonged signaling and contributes to its transforming ability. Previous studies have shown that the calcium pump, PMCA2, interacts with HER2 within membrane protrusions and is required for the retention of HER2 on the cell surface. In this study, we knocked down NHERF1 expression in breast cancer cells lines and examined whether the scaffolding protein, NHERF1, interacts with PMCA2 and HER2. We found that NHERF1 interacts with the PDZ-binding motif in PMCA2 in both normal and malignant breast cells, and that NHERF1 expression is increased in HER2-positive breast cancers and correlates with HER2-positive status in human DCIS lesions and invasive breast cancers, as well as with increased mortality in patients. Our results suggest that NHERF1 is part of a multiprotein complex that includes PMCA2, HSP90 and HER2 within specific actin-rich and lipid raft-rich membrane signaling domains. Reducing NHERF1 expression reduces PMCA2 and HER2 expression, inhibits HER2 signaling, dissociates HER2 from HSP90, and causes the internalization, ubiquitination and degradation of HER2. These results demonstrate that NHERF1 acts with PMCA2 to regulate HER2 signaling and membrane retention and implicates interactions between NHERF1 and PMCA2 as potential therapeutic targets in breast cancers.

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