biostudies-literatureMilitsin RTechnion-Israel Institute of TechnologyIsraeli Science FoundationRappaport Institutee202411203https://www.ebi.ac.uk/biostudies/studies/S-EPMC12302952biostudies-literatureUnknown224(9)Calcium ions (Ca2+) are crucial second messengers involved in numerous processes including tumorigenesis and cancer cell migration. Previous studies have shown that the endoplasmic reticulum (ER) Ca2+ sensors, stromal interaction molecules STIM1 and STIM2, are key regulators of cancer cell migration. In this study, using breast cancer cells lacking one or both STIM isoforms we show that although STIM proteins are critical regulators of cell migration, they are dispensable for this cellular activity. The mechanism underlying this complex effect involves functional crosstalk between STIM proteins and inositol 1,4,5-trisphosphate receptors (IP3Rs). Our findings indicate that beyond their classical role in store-operated Ca2+ entry, STIM proteins shape the spatial dynamics of IP3R-mediated Ca2The Journal of cell biologySTIM-IP3R crosstalk regulates migration of breast cancer cells.PMC123029522123/22Achildiev Cohen HMilitsin RYifat Raz APalty RShaked YDrori SLevi OHershfinkel MfalseSTIM-IP3R crosstalk regulates migration of breast cancer cells.Calcium ions (Ca2+) are crucial second messengers involved in numerous processes including tumorigenesis and cancer cell migration. Previous studies have shown that the endoplasmic reticulum (ER) Ca2+ sensors, stromal interaction molecules STIM1 and STIM2, are key regulators of cancer cell migration. In this study, using breast cancer cells lacking one or both STIM isoforms we show that although STIM proteins are critical regulators of cell migration, they are dispensable for this cellular activity. The mechanism underlying this complex effect involves functional crosstalk between STIM proteins and inositol 1,4,5-trisphosphate receptors (IP3Rs). Our findings indicate that beyond their classical role in store-operated Ca2+ entry, STIM proteins shape the spatial dynamics of IP3R-mediated Ca22025-01-01T00:00:00Z2025 Sep2026-03-27T17:01:15.175Z2025-08-28T03:09:11.418ZS-EPMC123029524071969910.1083/jcb.202411203