Very recent studies hold promise to reveal the role of stromal interaction molecule 1 (STIM1) in non-store-operated Ca2+ entry.Here we showed that in contrast to cytoplasmic membrane redistribution as previously noted,human umbilical vein endothelial STIM1 with a T-to-C nucleotide transition resulting in an amino acid substitution of leucine by proline in the signal peptide sequence translocated to perinuclear membrane upon intracellular Ca2+ depletion,amplified nucleoplasmic Ca2+ signaling through ryanodine receptors-dependent pathway,enhanced the subsequent cAMP responsive dement binding protein activity,matrix metalloproteinase-2 (MMP-2) gene expression and endothelial tube forming.