STIM proteins: integrators of signalling pathways in development, differentiation and disease

Introduction Part I: STIM proteins STIM1 and SOCE Setting the level of SOCE: expression levels of STIM1 and ORAI1 STIM1 and the regulation of other proteins at the plasma membrane STIM2 and SOCE Part II: STIM proteins and the regulation of cell physiology and pathology Immune system Skeletal muscle Smooth muscle Nervous system Adipose tissue Cancer Part III: invertebrate animal models of STIM deficiency D. melanogaster C. elegans Part IV: conclusions and future perspectives The stromal interaction molecules STIM1 and STIM2 are endoplasmic reticulum Ca2+ sensors, serving to detect changes in receptor-mediated ER Ca2+ store depletion and to relay this information to plasma membrane localized proteins, including the store-operated Ca2+ channels of the ORAI family. The resulting Ca2+ influx sustains the high cytosolic Ca2+ levels required for activation of many intracellular signal transducers such as the NFAT family of transcription factors. Models of STIM protein deficiency in mice, Drosophila melanogaster and Caenorhabditis elegans, in addition to the phenotype of patients bearing mutations in STIM1 have provided great insight into the role of these proteins in cell physiology and pathology. It is now becoming clear that STIM1 and STIM2 are critical for the development and functioning of many cell types, including lymphocytes, skeletal and smooth muscle myoblasts, adipocytes and neurons, and can interact with a variety of signalling proteins and pathways in a cell- and tissue-type specific manner. This review focuses on the role of STIM proteins in development, differentiation and disease, in particular highlighting the functional differences between STIM1 and STIM2.