Cab45S promotes cell proliferation through SERCA2b inhibition and Ca2+ signaling
Cab45S promotes cell proliferation through SERCA2b inhibition and Ca2+ signaling
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Cab45S 通过 SERCA2b 抑制和 Ca2 信号传导促进细胞增殖
DOI：
10.1038/onc.2015.56
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发表时间：
2016-01-07
期刊：
影响因子：
8
通讯作者：
Chen, J.
中科院分区：
文献类型：
--
作者：
Chen, L.;Xu, S.;Chen, J.
胞浆ca2 +与内质网ca2 +密切相关，在调节细胞增殖和肿瘤发生中起关键作用。然而，内质网管蛋白在调节胞浆ca2 +水平中的作用仍然知之甚少。在这里，我们发现Cab45S定位于内质网腔，通过其第一个EF-hand结构域直接结合SERCA2b的腔内环4，抑制sarco/ER ca2 +- atp酶2b （SERCA2b）的活性，并降低ER ca2 +。由cab45s依赖性ER ca2 +下降诱导的STIM1激活，以及质膜ca2 +通道TRPC1的上调，最终增加细胞外ca2 +内流。此外，胞质ca2 +水平升高引发ca2 +-NFAT信号传导，促进细胞增殖。一致地，在宫颈癌患者中，Cab45S表达上调。因此，我们的数据显示，Cab45S抑制SERCA2b活性的能力对于其作为细胞增殖和肿瘤生长调节剂的作用至关重要。
Cytosolic Ca 2+, closely related to endoplasmic reticulum (ER) Ca 2+, plays a critical role in regulating cell proliferation and tumorigenesis. However, the role of ER lumen proteins in regulating cytosolic Ca 2+ level remains poorly understood. Here, we find that the Cab45S, localizes in the ER lumen, inhibits sarco/ER Ca 2+-ATPase 2b (SERCA2b) activity through its first EF-hand domain directly binding to the intra-lumenal loop 4 of SERCA2b, and reduces ER Ca 2+. STIM1 activation, induced by the Cab45S-dependent drop in ER Ca 2+, together with the upregulation of the plasma membrane Ca 2+ channel TRPC1 ultimately increases extracellular Ca 2+ influx. Furthermore, increased cytosolic Ca 2+ level elicits Ca 2+-NFAT signaling and promotes cell proliferation. Consistently, in cervical carcinoma patients, Cab45S is upregulated. Thus, our data reveal that the ability of Cab45S to inhibit SERCA2b activity is crucial for its role as a modulator of cell proliferation and tumor growth.