STIM1 is a calcium sensor protein anchored in the endoplasmic reticulum (ER) membrane that regulates store-operated calcium entry (SOCE), a critical calcium influx pathway in cells 1. Upon depletion of intracellular calcium stores, STIM1 translocates to the plasma membrane where it directly binds to and activates calcium release-activated calcium (CRAC) channels, particularly the pore-forming subunit ORAI1, to mediate sustained calcium influx 12. This STIM1-ORAI1 interaction occurs within specialized membrane microdomains where the ER and plasma membrane come into close apposition 3. STIM1 also regulates transient receptor potential canonical (TRPC) channels, though TRPC activation can occur independently of STIM1 4. Loss-of-function mutations in STIM1 cause CRAC channelopathies characterized by abolished calcium entry and clinical manifestations including immunodeficiency, congenital myopathy, and anhydrotic ectodermal dysplasia 1. Beyond immune function, dysregulated STIM1-mediated calcium signaling contributes to stroke pathogenesis and cancer progression, where elevated STIM1 expression promotes tumor metastasis through effects on invadopodia formation, angiogenesis, and inflammatory responses 56. STIM1 protein stability is regulated by ubiquitination, providing potential therapeutic targets for conditions involving aberrant STIM1 signaling 7.