Protein-tyrosine phosphatase 1B potentiates IRE1 signaling during endoplasmic reticulum stress
Protein-tyrosine phosphatase 1B potentiates IRE1 signaling during endoplasmic reticulum stress
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DOI：
10.1074/jbc.c400261200
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发表时间：
2004-11-26
影响因子：
4.8
通讯作者：
Chevet, E
中科院分区：
文献类型：
--
作者：
Gu, F;Nguyên, DT;Chevet, E
蛋白酪氨酸磷酸酶1B（PTP-1B）是一种典型的酪氨酸磷酸酶，其在胰岛素信号传导和代谢中的功能已得到充分证实。虽然PTP-1B在去磷酸化各种细胞表面受体酪氨酸激酶中的作用是清楚的，但其调节内质网（ER）受体功能的机制仍然是一个谜。在这里，我们提供的证据表明，PTP-1B在调节未折叠的蛋白质反应在ER隔室中具有重要的功能。PTP-1B的缺乏导致ER应激诱导的IRE 1信号转导受损。更具体地说，JNK激活，XBP-1剪接，和EDEM（ER降解增强α-甘露糖苷酶样蛋白）基因诱导，以及ER应激诱导的细胞凋亡，在PTP-1B敲除小鼠胚胎成纤维细胞中响应于两种ER应激物衣霉素和氮杂环丁烷-2羧酸而减弱。我们证明，PTP-1B不仅是一个被动的居民的ER，但相反，在增强IRE 1介导的ER应激信号通路中起着至关重要的作用。
Protein-tyrosine phosphatase 1B (PTP-1B) is the prototypic tyrosine phosphatase whose function in insulin signaling and metabolism is well established. Although the role of PTP-1B in dephosphorylating various cell surface receptor tyrosine kinases is clear, the mechanisms by which it modulates receptor function from the endoplasmic reticulum (ER) remains an enigma. Here, we provide evidence that PTP-1B has an essential function in regulating the unfolded protein response in the ER compartment. The absence of PTP-1B caused impaired ER stress-induced IRE1 signaling. More specifically, JNK activation, XBP-1 splicing, and EDEM (ER degradation-enhancing alpha-mannosidase-like protein) gene induction, as well as ER stress-induced apoptosis, were attenuated in PTP-1B knock-out mouse embryonic fibroblasts in response to two ER stressors, tunicamycin and azetidine-2 carboxylic acid. We demonstrate that PTP-1B is not just a passive resident of the ER but on the contrary has an essential role in potentiating IRE1-mediated ER stress signaling pathways.