期刊
JOURNAL OF CELL SCIENCE
卷 126, 期 5, 页码 1260-1267出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.121129
关键词
Stromal-interaction molecule 1; Actomyosin; Contractile force; Microfabricated post-array detectors
类别
资金
- National Science Council [NSC 101-2321-B-006-019]
- National Health Research Institutes [NHRI-EX102-10243BI]
- Department of Health, Executive Yuan
- National Cheng Kung University Hospital, Taiwan
Stromal interaction molecule 1 (STIM1) is an endoplasmic reticulum (ER) Ca2+ sensor that triggers the store-operated Ca2+ entry (SOCE). The clinical relevance of STIM1 has been highlighted in breast and cervical cancer, but the molecular mechanism by which STIM1 promotes cancer progression remains unclear. This study explores the regulatory mechanisms by which STIM1-dependent Ca2+ signaling controls cancer cell migration. Three different SOCE inhibitors, SKF96365, 2-APB and YM-58483, significantly inhibited cervical cancer cell migration to a similar extent to that of STIM1 silencing. In contrast, STIM1 overexpression significantly enhanced cervical cancer cell migration. Live cell confocal images and three-dimensional tomograms showed that STIM1 formed aggregates and translocated towards the plasma membranes of migratory cells, and this was accompanied by increasing cytosolic Ca2+ spikes. STIM1 silencing also inhibited the recruitment and association of active focal adhesion kinase (pTyr397-FAK) and talin at focal adhesions, indicating the blockade of force transduction from integrin signaling. Epidermal growth factor-induced phosphorylation of myosin II regulatory light chains was abolished by STIM1 knockdown and SOCE inhibition. Dual immunostaining of activated myosin II (pSer19-MLC) and actin revealed that actomyosin formation depended on STIM1-mediated Ca2+ entry. Most importantly, STIM1 expression levels as well as SOCE activity controlled the generation of cell contractile force, as measured by the microfabricated post-array-detector system. These results highlight the unique role of STIM1-dependent Ca2+ signaling in controlling cell migration by the regulation of actomyosin reorganization in conjunction with enhanced contractile forces.
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