The STIM1 Phosphorylation Saga

Store-operated Ca²⁺ entry (SOCE) is a Ca²⁺ influx pathway present in practically every cell type in metazoans and mediates a variety of physiological functions. Defects in SOCE are associated with immunodeficiencies and defects in skeletal muscle development and function. The molecular machinery underpinning SOCE can be complex and cell type specific, however the minimal functional SOCE unit consists of the endoplasmic reticulum (ER) Ca²⁺ sensor STIM1 and the plasma membrane (PM) Ca²⁺-selective channel Orai1. STIM1 localizes to ER-PM contact sites (CS) following store depletion, where it recruits and gates Orai1. STIM1 is a phosphoprotein that is hyper-phosphorylated during cell division. STIM1 phosphorylation has been implicated in several functions, including modulation of cellular metabolism, SOCE inactivation during M-phase, ER segregation during mitosis, modulation of SOCE levels, and cell migration. However, the role of STIM1 phosphorylation in the majority of these processes is controversial bringing into question the physiological function of STIM1 phosphorylation, if any. Here we review the role and modulation of STIM1 phosphorylation under various conditions and argue that except for the modulation of energy metabolism, the physiological function of STIM1 phosphorylation remains unclear.