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基质相互作用分子-肌醇三磷酸受体相互作用调节乳腺癌细胞的迁移。

STIM-IP3R crosstalk regulates migration of breast cancer cells.

作者信息

Militsin Ruslana, Achildiev Cohen Hadas, Hershfinkel Maya, Levi Ofek, Drori Stavit, Yifat Raz Adi, Shaked Yuval, Palty Raz

机构信息

Department of Biochemistry, Technion Integrated Cancer Center, Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.

Department of Cell Biology and Cancer Science, Technion Integrated Cancer Center, Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.

出版信息

J Cell Biol. 2025 Sep 1;224(9). doi: 10.1083/jcb.202411203. Epub 2025 Jul 28.

DOI:10.1083/jcb.202411203
PMID:40719699
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12302952/
Abstract

Calcium ions (Ca2+) are crucial second messengers involved in numerous processes including tumorigenesis and cancer cell migration. Previous studies have shown that the endoplasmic reticulum (ER) Ca2+ sensors, stromal interaction molecules STIM1 and STIM2, are key regulators of cancer cell migration. In this study, using breast cancer cells lacking one or both STIM isoforms we show that although STIM proteins are critical regulators of cell migration, they are dispensable for this cellular activity. The mechanism underlying this complex effect involves functional crosstalk between STIM proteins and inositol 1,4,5-trisphosphate receptors (IP3Rs). Our findings indicate that beyond their classical role in store-operated Ca2+ entry, STIM proteins shape the spatial dynamics of IP3R-mediated Ca2+ release. Our results suggest that following ER Ca2+ depletion, the activated STIM proteins shift the pattern of IP3R-mediated Ca2+ release from a localized signal, which promotes cell migration, to a more diffuse signal, which attenuates cell migration.

摘要

钙离子（Ca2+）是至关重要的第二信使，参与包括肿瘤发生和癌细胞迁移在内的众多过程。先前的研究表明，内质网（ER）Ca2+传感器——基质相互作用分子1（STIM1）和基质相互作用分子2（STIM2）——是癌细胞迁移的关键调节因子。在本研究中，我们使用缺失一种或两种STIM亚型的乳腺癌细胞表明，尽管STIM蛋白是细胞迁移的关键调节因子，但它们对于这种细胞活动并非必不可少。这种复杂效应背后的机制涉及STIM蛋白与肌醇1,4,5-三磷酸受体（IP3Rs）之间的功能性串扰。我们的研究结果表明，除了在储存式Ca2+内流中的经典作用外，STIM蛋白还塑造了IP3R介导的Ca2+释放的空间动态。我们的结果表明，在内质网Ca2+耗竭后，活化的STIM蛋白将IP3R介导的Ca2+释放模式从促进细胞迁移的局部信号转变为减弱细胞迁移的更弥散信号。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/7c8ca17c08cb/jcb_202411203_figs5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/5e91dc647d06/jcb_202411203_figs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/80ecb006965d/jcb_202411203_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/5c19255957f4/jcb_202411203_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/e4efe702cc61/jcb_202411203_figs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/809b2fc01ad0/jcb_202411203_figs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/188ec05781d8/jcb_202411203_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/69a946ed70d3/jcb_202411203_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/f3883b28290e/jcb_202411203_figs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/f0d2c3468e2e/jcb_202411203_fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/7c8ca17c08cb/jcb_202411203_figs5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/5e91dc647d06/jcb_202411203_figs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/80ecb006965d/jcb_202411203_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/5c19255957f4/jcb_202411203_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/e4efe702cc61/jcb_202411203_figs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/809b2fc01ad0/jcb_202411203_figs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/188ec05781d8/jcb_202411203_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/69a946ed70d3/jcb_202411203_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/f3883b28290e/jcb_202411203_figs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/f0d2c3468e2e/jcb_202411203_fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ebf/12302952/7c8ca17c08cb/jcb_202411203_figs5.jpg

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本文引用的文献

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2
Ca2+ tunneling architecture and function are important for secretion.钙离子通道结构与功能对于分泌非常重要。
J Cell Biol. 2025 Jan 6;224(1). doi: 10.1083/jcb.202402107. Epub 2024 Nov 5.
3
Dual regulation of IP receptors by IP and PIP controls the transition from local to global Ca signals.
双重调节 IP 受体的 IP 和 PIP 控制着从局部到全局 Ca 信号的转变。
Mol Cell. 2024 Oct 17;84(20):3997-4015.e7. doi: 10.1016/j.molcel.2024.09.009. Epub 2024 Oct 3.
4
Endoplasmic reticulum-plasma membrane contact gradients direct cell migration.内质网-质膜接触梯度指导细胞迁移。
Nature. 2024 Jul;631(8020):415-423. doi: 10.1038/s41586-024-07527-5. Epub 2024 Jun 12.
5
The ER stress sensor IRE1 interacts with STIM1 to promote store-operated calcium entry, T cell activation, and muscular differentiation.内质网应激传感器 IRE1 与 STIM1 相互作用，促进钙库操纵性钙内流、T 细胞激活和肌肉分化。
Cell Rep. 2023 Dec 26;42(12):113540. doi: 10.1016/j.celrep.2023.113540. Epub 2023 Dec 5.
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