The STIM family of proteins plays a crucial role in a plethora of cellular functions through the regulation of store-operated Ca²⁺ entry (SOCE) and, thus, intracellular calcium homeostasis. The two members of the mammalian STIM family, STIM1 and STIM2, are transmembrane proteins that act as Ca²⁺ sensors in the endoplasmic reticulum (ER) and, upon Ca²⁺ store discharge, interact with and activate the Orai/CRACs in the plasma membrane. Dysregulation of Ca²⁺ signaling leads to the pathogenesis of a variety of human diseases, including neurodegenerative disorders, cardiovascular diseases, cancer, and immune disorders. Therefore, understanding the mechanisms underlying Ca²⁺ signaling pathways is crucial for developing therapeutic strategies targeting these diseases. This review focuses on several rare conditions associated with STIM1 mutations that lead to either gain- or loss-of-function, characterized by myopathy, hematological and immunological disorders, among others, and due to abnormal activation of CRACs. In addition, we summarize the current evidence concerning STIM2 allele duplication and deletion associated with language, intellectual, and developmental delay, recurrent pulmonary infections, microcephaly, facial dimorphism, limb anomalies, hypogonadism, and congenital heart defects.

FLNA cleaving by calpain has been observed in a variety of tumoral, including prostate and colorectal cancer cells, as well as in nontumoral cells, leading to a C-terminal fragment encompassing repeats 16–24. Expression of the FLNA^16–24 fragment in HEK-293 cells enhances Orai1 and STIM1 expression, as well as SOCE, a mechanism mediated by attenuation of Orai1α and STIM1 degradation, providing evidence for a novel mechanism for the regulation of SOCE in normal and malignant cells.

Calcium signaling via store-operated calcium entry (SOCE) is critical for cellular functions implicated in cancer progression. Alterations in Orai channel isoforms, particularly Orai1 and Orai3, modulate SOCE and influence tumor cell proliferation, invasion, and survival. Here, we review and synthesize current evidence showing how Orai1 and Orai3 isoforms modulate oncogenic calcium signals through pathways such as phosphatidylinositol 3-kinase (PI3K)/Akt, ERK1/2, and NF-κB, contributing to tumor progression and chemoresistance by regulating apoptosis, autophagy, and oxidative stress responses. This isoform-specific remodeling enables tumor cells to adapt to therapeutic challenges and oxidative environments. Emerging data suggest that modulating Orai channel function and isoform composition may sensitize some cancer cells to apoptosis and attenuate invasive behavior, at least in specific experimental models. Taken together, available studies support a role for Orai channels as important regulators of tumor-associated Ca ²⁺ signaling and highlight their potential as context-dependent targets to modulate survival and invasive behavior in cancer models.

Extended synaptotagmins (E-Syts) are endoplasmic reticulum (ER)-associated proteins that facilitate the tethering of the ER to the plasma membrane (PM), participating in lipid transfer between the membranes and supporting the Orai1–STIM1 interaction at ER–PM junctions. Orai1 and STIM1 are the core proteins of store-operated Ca²⁺ entry (SOCE), a major mechanism for Ca²⁺ influx that regulates a variety of cellular functions. Aberrant modulation of SOCE in cells from different types of cancer has been reported to underlie the development of several tumoral features. Here we show that estrogen receptor-positive (ER+) breast cancer MCF7 and T47D cells and triple-negative breast cancer (TNBC) MDA-MB-231 cells overexpress E-Syt1 and E-Syt2 at the protein level; the latter is also overexpressed in the TNBC BT20 cell line. E-Syt1 and E-Syt2 knockdown was without effect on SOCE in non-tumoral MCF10A breast epithelial cells and ER+ T47D breast cancer cells; however, SOCE was significantly attenuated in ER+ MCF7 cells and TNBC MDA-MB-231 and BT20 cells upon transfection with siRNA E-Syt1 or E-Syt2. Consistent with this, E-Syt1 and E-Syt2 knockdown significantly reduced cell migration and viability in ER+ MCF7 cells and the TNBC cells investigated. To summarize, E-Syt1 and E-Syt2 play a relevant functional role in breast cancer cells.

Store-operated Ca ²⁺ entry (SOCE) is a mechanism controlled by the filling state of the intracellular Ca ²⁺ stores, predominantly the endoplasmic reticulum (ER), where ER-resident proteins STIM1 and STIM2 orchestrate the activation of Orai channels in the plasma membrane, and Orai1 playing a predominant role. Two forms of Orai1, Orai1α and Orai1β, have been identified, which arises the question whether they are equally regulated by STIM proteins. We demonstrate that STIM1 preferentially activates Orai1α over STIM2, yet both STIM proteins similarly activate Orai1β. Under resting conditions, there is a pronounced association between STIM2 and Orai1α, implying their significance in maintaining basal Ca ²⁺ levels within the cytosol and ER. STIM1 and STIM2 are also shown to influence the protein levels of the Orai1 variants, independent of Ca ²⁺ influx, via lysosomal degradation. Interestingly, Orai1α and Orai1β appear to selectively regulate the protein level of STIM1, but not STIM2. These observations offer crucial insights into the regulatory dynamics between STIM proteins and Orai1 variants, enhancing our understanding of the intricate processes that fine-tune intracellular Ca ²⁺ signaling.

Orai1 and Orai3 exert opposing effects on the PI3K/Akt1 pathway, revealing a complex regulatory mechanism to coordinate cellular processes, such as survival, in ER+ breast cancer cells. Although Orai3 promotes Akt1 activation via CaMKK to drive tumor progression, Orai1 acts as a modulator on this axis through an AC8/cAMP-dependent mechanism. These findings highlight the functional diversity of Orai proteins and identify them as potential therapeutic targets for modulating Akt1-driven aggressiveness in breast cancer.