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Figure 7 | BMC Cancer

Figure 7

From: Targeting cell migration and the endoplasmic reticulum stress response with calmodulin antagonists: a clinically tested small molecule phenocopy of SEC62 gene silencing in human tumor cells

Figure 7

Model for Sec62’s influence on ER Ca 2+ efflux via the Sec61 complex under various conditions. A, Physiological situation: most Sec61 complexes are associated with Sec62/Sec63-complexes. Calcium ions (Ca2+) leaking through the channel to the cytosol are detected by Sec62‘s EF hand, thus facilitating an interaction between Ca2+-CaM and the Sec61 complex and subsequent sealing of the channel. Sec62/Sec63-free Sec61 complexes allow a basal leakage of Ca2+, which is counteracted by SERCA activity. B, SEC62 knockdown conditions: depletion of Sec62 leads to a lack of calcium detection by Sec62 on the cytosolic surface of the ER. Ca2+-CaM is no longer recruited to the Sec61 complex and Ca2+ leakage persists, resulting in a slightly increased cytosolic Ca2+ concentration and a predisposition of the cells to apoptosis. Hence, Ca2+-dependent cell migration is inhibited. C, Compared with the situation described in B, the SERCA pump is inhibited by thapsigargin. The increased leakage combined with the inactivated back-pumping leads to a dramatic elevation in the cytosolic Ca2+ concentration and the cells undergo apoptosis. D, Trifluoperazine conditions: the situation described in B and C is mimicked by TFP treatment. Here, Sec62 still detects the leaking Ca2+, but the Ca2+-CaM-Sec61 complex interaction is blocked by TFP. In the absence of thapsigargin, the lack of interaction leads to the situation described in B; in the presence of thapsigargin, it leads to the situation described in C. E, Pathophysiological situation: an increased level of Sec62 protein probably leads to sealing of more Sec61 complexes, which may reduce the cytosolic Ca2+ level and/or increase the ER Ca2+ concentration, thereby protecting the cells against thapsigargin-induced ER stress.

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