TY - JOUR
T1 - The scaffolding protein NHERF1 regulates the stability and activity of the tyrosine kinase HER2
AU - Jeong, Jaekwang
AU - VanHouten, Joshua N.
AU - Kim, Wonnam
AU - Dann, Pamela
AU - Sullivan, Catherine
AU - Choi, Jungmin
AU - Sneddon, W. Bruce
AU - Friedman, Peter A.
AU - Wysolmerski, John J.
N1 - Funding Information:
This work was supported by National Institutes of Health Grants CA153702 and HD076248 (to J. J. W.) and DK105811 (to P. A. F.)
Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2017/4/21
Y1 - 2017/4/21
N2 - Weexamined whether the scaffolding protein sodium-hydrogen exchanger regulatory factor 1 (NHERF1) interacts with the calcium pump PMCA2 and the tyrosine kinase receptor ErbB2/ HER2 in normal mammary epithelial cells and breast cancer cells. NHERF1 interacts with the PDZ-binding motif in PMCA2 in both normal and malignant breast cells. NHERF1 expression is increased in HER2-positive breast cancers and correlates with HER2-positive status in human ductal carcinoma in situ (DCIS) lesions and invasive breast cancers as well as with increased mortality in patients. NHERF1 is part of a multiprotein complex that includes PMCA2, HSP90, and HER2 within specific actinrich and lipid raft-rich membrane signaling domains. Knocking down NHERF1 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 in breast cancers.
AB - Weexamined whether the scaffolding protein sodium-hydrogen exchanger regulatory factor 1 (NHERF1) interacts with the calcium pump PMCA2 and the tyrosine kinase receptor ErbB2/ HER2 in normal mammary epithelial cells and breast cancer cells. NHERF1 interacts with the PDZ-binding motif in PMCA2 in both normal and malignant breast cells. NHERF1 expression is increased in HER2-positive breast cancers and correlates with HER2-positive status in human ductal carcinoma in situ (DCIS) lesions and invasive breast cancers as well as with increased mortality in patients. NHERF1 is part of a multiprotein complex that includes PMCA2, HSP90, and HER2 within specific actinrich and lipid raft-rich membrane signaling domains. Knocking down NHERF1 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 in breast cancers.
UR - http://www.scopus.com/inward/record.url?scp=85018543781&partnerID=8YFLogxK
U2 - 10.1074/jbc.M116.770883
DO - 10.1074/jbc.M116.770883
M3 - Article
C2 - 28235801
AN - SCOPUS:85018543781
SN - 0021-9258
VL - 292
SP - 6555
EP - 6568
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 16
ER -
