STIM proteins at the intersection of signaling pathways

The endoplasmic reticulum (ER) is a vast intracellular organelle important to maintain proteome, lipid and calcium homeostasis to ensure cellular functionality. Stromal Interaction Molecule (STIM) proteins are sensors that can respond to changes in ER Ca2+ concentration with conformational change, oligomerization and relocalization to ER–plasma membrane (PM) contact sites. Here they gate and regulate highly Ca2+ selective Orai channels. Besides these canonical functions, STIM proteins can also anchor proteins in the ER, shape the ER through their interaction with microtubules and bind to other cytosolic and ER-luminal proteins. This review focuses on the role of STIM proteins at intersections of signaling pathways. Three aspects will be covered: The role of STIM proteins to expand the ER by interactions with microtubules and actin networks, STIM mediated crosstalk between Ca2+ and cAMP second messenger signaling systems as well as crosstalk between STIM and the energy sensing enzyme 5′-AMP-activated protein kinase (AMPK).