Kimmel Center for Biology and Medicine at the Skirball Institute and Department of Cell Biology, NYU School of Medicine, 540 First Avenue, New York, NY 10016, USA.
Kimmel Center for Biology and Medicine at the Skirball Institute and Department of Cell Biology, NYU School of Medicine, 540 First Avenue, New York, NY 10016, USA.
Cell Rep. 2019 Jan 8;26(2):322-329.e3. doi: 10.1016/j.celrep.2018.12.049.
Calcium homeostasis in the lumen of the endoplasmic reticulum is required for correct processing and trafficking of transmembrane proteins, and defects in protein trafficking can impinge on cell signaling pathways. We show here that mutations in the endoplasmic reticulum calcium pump SERCA disrupt Wingless signaling by sequestering Armadillo/β-catenin away from the signaling pool. Armadillo remains bound to E-cadherin, which is retained in the endoplasmic reticulum when calcium levels there are reduced. Using hypomorphic and null SERCA alleles in combination with the loss of the plasma membrane calcium channel Orai allowed us to define three distinct thresholds of endoplasmic reticulum calcium. Wingless signaling is sensitive to even a small reduction, while Notch and Hippo signaling are disrupted at intermediate levels, and elimination of SERCA function results in apoptosis. These differential and opposing effects on three oncogenic signaling pathways may complicate the use of SERCA inhibitors as cancer therapeutics.
内质网腔中的钙稳态对于跨膜蛋白的正确加工和运输是必需的，而蛋白质运输的缺陷会影响细胞信号通路。我们在这里表明，内质网钙泵 SERCA 的突变通过将 Armadillo/β-catenin 隔离在信号池之外来破坏 Wnt 信号。当内质网中的钙水平降低时，Armadillo 仍然与 E-cadherin 结合，E-cadherin 保留在内质网中。使用功能减弱和缺失的 SERCA 等位基因与质膜钙通道 Orai 的缺失相结合，使我们能够定义三个不同的内质网钙阈值。Wnt 信号对即使很小的减少也很敏感，而 Notch 和 Hippo 信号在中间水平被破坏，SERCA 功能的消除导致细胞凋亡。这种对三种致癌信号通路的不同和相反的影响可能会使 SERCA 抑制剂作为癌症治疗药物的使用复杂化。
