Jeong Jaekwang, VanHouten Joshua N, Kim Wonnam, Dann Pamela, Sullivan Catherine, Choi Jungmin, Sneddon W Bruce, Friedman Peter A, Wysolmerski John J
From the Section of Endocrinology and Metabolism, Department of Internal Medicine.
Department of Pediatrics, and.
J Biol Chem. 2017 Apr 21;292(16):6555-6568. doi: 10.1074/jbc.M116.770883. Epub 2017 Feb 24.
We examined 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 (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 actin-rich 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.
我们研究了支架蛋白钠氢交换调节因子1（NHERF1）在正常乳腺上皮细胞和乳腺癌细胞中是否与钙泵PMCA2以及酪氨酸激酶受体ErbB2/HER2相互作用。在正常和恶性乳腺细胞中，NHERF1均与PMCA2中的PDZ结合基序相互作用。NHERF1在HER2阳性乳腺癌中表达增加，并且与人导管原位癌（DCIS）病变和浸润性乳腺癌中的HER2阳性状态相关，也与患者死亡率增加相关。NHERF1是一种多蛋白复合物的一部分，该复合物在特定的富含肌动蛋白和富含脂筏的膜信号域中包含PMCA2、HSP90和HER2。敲低NHERF1会降低PMCA2和HER2的表达，抑制HER2信号传导，使HER2与HSP90解离，并导致HER2的内化、泛素化和降解。这些结果表明，NHERF1与PMCA2共同作用以调节乳腺癌中的HER2信号传导和膜保留。
