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首页> 外文期刊>Cellular Signalling >HER2 regulates Brk/PTK6 stability via upregulating calpastatin, an inhibitor of calpain
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HER2 regulates Brk/PTK6 stability via upregulating calpastatin, an inhibitor of calpain

机译：HER2通过上调钙蛋白酶抑制剂钙蛋白酶抑制剂来调节Brk / PTK6稳定性

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摘要

Breast tumor kinase (Brk), also known as protein kinase-6 (PTK6), is a nonreceptor protein-tyrosine kinase that has a close functional relationship with the human epidermal growth factor receptor 2 (HER2). High levels of Brk were found in HER2-positive tumor specimens from patients with invasive ductal breast cancer; however, the underlying mechanism of the co-overexpression of Brk and HER2 remains elusive. In the current study, we explored the mechanism of HER2 and Brk co-overexpression in breast cancer cells by investigating the effect of overexpression and knockdown of HER2 on the level of Brk in breast cancer cells. We found that Brk was more stable in HER2-elevated cells than in control vector-transfected cells and was less stable in HER2 siRNA-treated cells than in control siRNA-treated cells, suggesting that HER2 regulates Brk protein stability. Further studies indicated that degradation of Brk involved a calpain-1-mediated proteolytic pathway and indicated an inverse relationship between the level of HER2 expression and calpain-1 activity. We found that HER2 inhibited calpain-1 activity through upregulating calpastatin, an endogenous calpain inhibitor. Silencing of HER2 downregulated calpastatin, and the downregulation could be rescued by overexpression of constitutively active MEK. Together, these data offer novel mechanistic insights into the functional relationship between Brk and HER2.
机译：乳腺癌肿瘤激酶（Brk），也称为蛋白激酶6（PTK6），是一种非受体蛋白酪氨酸激酶，与人表皮生长因子受体2（HER2）的功能密切相关。在浸润性导管癌患者的HER2阳性肿瘤标本中发现高水平的Brk。但是，Brk和HER2共同表达的潜在机制仍然难以捉摸。在当前的研究中，我们通过研究HER2的过表达和敲除对乳腺癌细胞中Brk水平的影响，探索了HER2和Brk在乳腺癌细胞中共过量表达的机制。我们发现Brk在HER2升高的细胞中比在对照载体转染的细胞中更稳定，并且在HER2 siRNA处理的细胞中比在对照siRNA处理的细胞中更不稳定，表明HER2调节Brk蛋白的稳定性。进一步的研究表明Brk的降解涉及钙蛋白酶1介导的蛋白水解途径，并表明HER2表达水平与钙蛋白酶1活性呈反比关系。我们发现HER2通过上调钙蛋白酶抑制素（一种内源性钙蛋白酶抑制剂）抑制钙蛋白酶-1的活性。沉默HER2下调的钙调他汀，并通过过度表达组成型活性MEK来挽救下调。这些数据一起为Brk和HER2之间的功能关系提供了新颖的机械原理。

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