SUMMARY Ca2+ is an essential and ubiquitous second messenger. Changes in cytosolic Ca2+ trigger events critical for tumorigenesis, such as cellular motility, proliferation and apoptosis. We show that an isoform of Secretory Pathway Ca2+-ATPase, SPCA2, is upregulated in breast cancer-derived cells and human breast tumors, and suppression of SPCA2 attenuated basal Ca2+ levels and tumorigenicity. Contrary to its conventional role in Golgi Ca2+ sequestration, expression of SPCA2 increased Ca2+ influx by a mechanism dependent on the store-operated Ca2+ channel Orai1. Unexpectedly, SPCA2-Orai1 signaling was independent of ER Ca2+ stores or STIM1 and STIM2 sensors, and uncoupled from Ca2+-ATPase activity of SPCA2. Binding of SPCA2 amino terminus to Orai1 enabled access of its carboxyl terminus to Orai1 and activation of Ca2+ influx. Our findings reveal a signaling pathway in which Orai1-SPCA2 complex elicits constitutive store-independent Ca2+ signaling that promotes tumorigenesis.

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This paper investigates the accuracy of the so-called Modified Manson-Coffin Curve Method (MMCCM) in estimating fatigue lifetime of metallic materials subjected to complex constant and variable amplitude multiaxial load histories. The MMCCM postulates that fatigue damage is maximised on that material plane experiencing the maximum shear strain amplitude. In the present investigation, the orientation of the critical plane was determined through that direction along which the variance of the resolved shear strain reaches it maximum value. Under variable amplitude complex load histories, this direction was also used to count the resolved shear strain cycles via the classic Rain-Flow method. Further, the degree of multiaxiality and nonproportionality of the time-variable stress states at the assumed critical locations was directly quantified through a suitable stress ratio which accounts for (i) the mean value and the variance of the stress perpendicular to the critical plane as well as for (ii) the variance of the shear stress resolved along the direction experiencing the maximum variance of the resolved shear strain. The accuracy and reliability of the proposed approach was checked against approximately 650 experimental data taken from the literature and generated by testing un-notched metallic materials under complex constant and variable amplitude multiaxial load histories. The sound agreement between estimates and experimental results which was obtained strongly supports the idea that the proposed design technique is a powerful engineering tool allowing metallic materials to be designed against constant and variable amplitude multiaxial fatigue by always reaching a remarkable level of accuracy. This approach offers a complete solution to the strain based multiaxial fatigue problem.

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