Store-operated calcium entry (SOCE) is the predominant Ca2+ entry mechanism
in nonexcitable cells and controls a variety of physiological and pathological processes. Although
significant progress has been made in identifying the components required for SOCE,
the molecular mechanisms underlying it are elusive. The present study provides evidence for
a direct involvement of kinase suppressor of Ras 2 (KSR2) in SOCE. Using lymphocytes and
fibroblasts from ksr2−/− mice and shKSR2-depleted cells, we find that KSR2 is critical for the
elevation of cytosolic Ca2+ concentration. Specifically, our results show that although it is
dispensable for Ca2+-store depletion, KSR2 is required for optimal calcium entry. We observe
that KSR2 deficiency affects stromal interaction molecule 1 (STIM1)/ORAI1 puncta formation,
which is correlated with cytoskeleton disorganization. Of interest, we find that KSR2-associated
calcineurin is crucial for SOCE. Blocking calcineurin activity impairs STIM1/ORAI1 puncta-like
formation and cytoskeleton organization. In addition, we observe that calcineurin
activity and its role in SOCE are both KSR2 dependent.
