The ER Ca2+ sensor STIM1 regulates actomyosin contractility of migratory cells

Abstract

Summary Stromal interaction molecule 1 (STIM1) is an endoplasmic reticulum (ER) Ca2+ sensor that triggers the store-operated Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ signaling in controlling cell migration by the regulation of actomyosin reorganization in conjunction with enhanced contractile forces.

Remodelling of Ca2+transport in cancer: how it contributes to cancer hallmarks?

“…Enhanced STIM1-ORAI1-mediated SOCE promoted higher rate of focal adhesion turnover and fast migration of metastatic breast cancer cells via activation of GTPases Ras and Rac [76] and of cervical cancer cells via engagement of calpain and PYK2 [13]. Higher migration of cervical cancer cells owing to STIM1 overexpression was shown to correlate with its accumulation in the ER punctae translocated towards plasma membrane of migratory cells and increasing cytosolic Ca 2þ spikes [78]. This resulted in more effective recruitment and association of active focal adhesion kinase (pTyr397-FAK) and talin at focal adhesions to facilitate force transduction from integrin signalling, and to promote actomyosin formation [78].…”

Elevated Orai1 expression mediates tumor-promoting intracellular Ca2+ oscillations in human esophageal squamous cell carcinoma

“…For example, STIM1 was reported to promote cell proliferation and migration, to favor the development of angiogenesis in cervical cancer, and to enhance focal adhesion turnover in breast cancer cells [13, 14, 31]. Chen et al , who examined tumor tissues from subjects with early-stage cervical cancer, observed that STIM1 was overexpressed in 71% of these tissues [14].…”

The store-operated calcium channels in cancer metastasis from cell migration invasion to metastatic colonization

“…RasGRF1, RasGFR2, RasGRP) are activated by binding to Ca2 + or calmodulin, and thus could potentially mediate the activation of small GTPase downstream of SOCE (Figure 1). SOCE may also control focal adhesion turnover through focal adhesion kinases FAK and Pyk2, since SOCE inhibition also decreases the levels of active FAK and Pyk2 (36, 41, 77). FAK has no Ca2 + or calmodulin binding motif, and therefore FAK is likely to be regulated by SOCE indirectly.…”