HER2 signaling regulates HER2 localization and membrane retention.
HER2 signaling regulates HER2 localization and membrane retention.
复制标题
DOI：
10.1371/journal.pone.0174849
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Wysolmerski JJ
中科院分区：
文献类型：
--
作者：
Jeong J;Kim W;Kim LK;VanHouten J;Wysolmerski JJ
ErbB 2/HER 2/Neu是一种受体酪氨酸激酶，在25-30%的人乳腺癌中过表达，通常与ERBB 2基因扩增相关。HER 2没有公认的配体，HER 2和EGFR（ErbB 1/HER 1）或HER 2和ErbB 3/HER 3之间的异二聚体在乳腺癌中很重要。与其他ErbB家族成员不同，HER 2对内化和降解具有抗性，并在激活后长时间留在细胞表面以发出信号。尽管HER 2在细胞表面滞留的机制尚未完全了解，但先前的研究表明，为了避免内化，HER 2必须与从细胞表面突出的特定质膜结构域内的伴侣蛋白HSP 90和钙泵PMCA 2相互作用。在本报告中，我们证明HER 2信号传导本身对于膜突起的形成和维持至关重要，至少部分是通过维持PMCA 2表达和防止细胞内钙浓度增加来实现的。HER 2表达的部分基因敲除或HER 2信号传导的药理学抑制导致膜突起的消耗和HER 2与HSP 90之间的相互作用的破坏。这与HER 2的泛素化、其与EGFR或HER 3的内化及其降解有关。这些结果提示了一种模型，通过该模型，HER 2信号传导的一些阈值对于多蛋白信号传导复合物的形成和/或维持是必需的，所述多蛋白信号传导复合物通过抑制HER 2泛素化和内化来增强和延长HER 2/EGFR或HER 2/HER 3信号传导。
ErbB2/HER2/Neu is a receptor tyrosine kinase that is overexpressed in 25–30% of human breast cancers, usually associated with amplification of the ERBB2 gene. HER2 has no recognized ligands and heterodimers between HER2 and EGFR (ErbB1/HER1) or HER2 and ErbB3/HER3 are important in breast cancer. Unlike other ErbB family members, HER2 is resistant to internalization and degradation, and remains at the cell surface to signal for prolonged periods after it is activated. Although the mechanisms underlying retention of HER2 at the cell surface are not fully understood, prior studies have shown that, in order to avoid internalization, HER2 must interact with the chaperone, HSP90, and the calcium pump, PMCA2, within specific plasma membrane domains that protrude from the cell surface. In this report, we demonstrate that HER2 signaling, itself, is important for the formation and maintenance of membrane protrusions, at least in part, by maintaining PMCA2 expression and preventing increased intracellular calcium concentrations. Partial genetic knockdown of HER2 expression or pharmacologic inhibition of HER2 signaling causes the depletion of membrane protrusions and disruption of the interactions between HER2 and HSP90. This is associated with the ubiquitination of HER2, its internalization with EGFR or HER3, and its degradation. These results suggest a model by which some threshold of HER2 signaling is required for the formation and/or maintenance of multi-protein signaling complexes that reinforce and prolong HER2/EGFR or HER2/HER3 signaling by inhibiting HER2 ubiquitination and internalization.