{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSTIM2 is an endoplasmic reticulum Ca²⁺ sensor that, like its well‐studied paralog STIM1, couples the status of ER Ca²⁺ stores to plasma membrane Ca²⁺ influx. However, STIM2 exhibits a distinct activation threshold, as it responds to only modest decreases in ER Ca²⁺ levels and plays a key role in setting and maintaining basal cytosolic and ER Ca²⁺ concentrations. This early sensing function, described in receptor‐mediated signaling paradigms, underscores its importance in tuning the amplitude of Ca²⁺ signals and supporting homeostatic as well as signal‐dependent Ca²⁺ entry."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role as a positive regulator of Ca²⁺ entry, STIM2 displays unique biophysical and structural features that distinguish it from STIM1. Studies reveal that its EF‐hand/sterile alpha‐motif (EF‐SAM) region has slower oligomerization kinetics and enhanced structural stability, while differences in the N-terminal and polybasic domains modify its interactions with phospholipids and the Orai channels. Moreover, STIM2 can participate in both store-operated and store-independent activation modes, and naturally occurring splice variants—such as STIM2.1—act as negative regulators by interfering with Orai1 channel cross-linking and modulating the strength and duration of Ca²⁺ signals."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "13"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its intrinsic Ca²⁺‐sensing and channel‐regulating capacities, STIM2 is implicated in diverse cellular processes and pathological contexts. In neurons, for instance, STIM2 mediates capacitive Ca²⁺ entry that contributes to ischemia‐induced Ca²⁺ overload and neuronal cell death, while its modulation can affect synaptic plasticity and network excitability. In nonexcitable cells such as T lymphocytes, epithelial cells, and myoblasts, STIM2 participates in the fine control of Ca²⁺ signaling that governs differentiation, proliferation, migration and even epithelial–mesenchymal transitions implicated in cancer. Its altered expression has been associated with apoptosis resistance in tumor cells and may influence disease progression in conditions ranging from autoimmune disorders and diabetic kidney injury to vascular remodeling and neurodegeneration. Moreover, by forming heteromeric complexes with STIM1 and interacting with partners such as Orai1, TRPC channels, and regulatory proteins (e.g., calmodulin and AKAP79), STIM2 fine-tunes both store-operated and alternative Ca²⁺ entry pathways that ultimately regulate Ca²⁺-dependent gene transcription and cellular homeostasis. This broad spectrum of functions and cellular contexts is reflected in studies that link STIM2 to regulation of redox signaling, maintenance of basal Ca²⁺ levels via pre-targeting to the plasma membrane, and even modulation by upstream signals like Notch, highlighting its potential as a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "42"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jen Liou, Man Lyang Kim, Won Do Heo, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "STIM2 is a feedback regulator that stabilizes basal cytosolic and endoplasmic reticulum Ca2+ levels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2007.11.039"}], "href": "https://doi.org/10.1016/j.cell.2007.11.039"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18160041"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18160041"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jonathan Soboloff, Brad S Rothberg, Muniswamy Madesh, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "STIM2 regulates capacitive Ca2+ entry in neurons and plays a key role in hypoxic neuronal cell death."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Signal (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scisignal.2000522"}], "href": "https://doi.org/10.1126/scisignal.2000522"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19843959"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19843959"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Jonathan Soboloff, Maria A Spassova, Thamara Hewavitharana, et al. "}, {"type": "b", "children": [{"type": "t", "text": "STIM2 is an inhibitor of STIM1-mediated store-operated Ca2+ Entry."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cub.2006.05.051"}], "href": "https://doi.org/10.1016/j.cub.2006.05.051"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16860747"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16860747"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Peter B Stathopulos, Le Zheng, Mitsuhiko Ikura "}, {"type": "b", "children": [{"type": "t", "text": "Stromal interaction molecule (STIM) 1 and STIM2 calcium sensing regions exhibit distinct unfolding and oligomerization kinetics."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.C800178200"}], "href": "https://doi.org/10.1074/jbc.C800178200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19019825"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19019825"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Xizhuo Wang, Youjun Wang, Yandong Zhou, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "A reciprocal shift in transient receptor potential channel 1 (TRPC1) and stromal interaction molecule 2 (STIM2) contributes to Ca2+ remodeling and cancer hallmarks in colorectal carcinoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M114.581678"}], "href": "https://doi.org/10.1074/jbc.M114.581678"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25143380"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25143380"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Anshul Rana, Michelle Yen, Amir Masoud Sadaghiani, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Human muscle economy myoblast differentiation and excitation-contraction coupling use the same molecular partners, STIM1 and STIM2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.118984"}], "href": "https://doi.org/10.1074/jbc.M110.118984"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20436167"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20436167"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Hanene Zbidi, Isaac Jardin, Geoffrey E Woodard, et al. 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