Nuclear calcium (Ca ²⁺ ) regulates a number of important cellular processes, including gene transcription, growth, and apoptosis. However, it is unclear whether Ca ²⁺ signaling is regulated differently in the nucleus and cytosol. To investigate this possibility, we examined subcellular mechanisms of Ca ²⁺ release in the HepG2 liver cell line. The type II isoform of the inositol 1,4,5-trisphosphate (InsP ₃ ) receptor (InsP ₃ R) was expressed to a similar extent in the endoplasmic reticulum and nucleus, whereas the type III InsP ₃ R was concentrated in the endoplasmic reticulum, and the type I isoform was not expressed. Ca ²⁺ signals induced by low InsP ₃ concentrations started earlier or were larger in the nucleus than in the cytosol, indicating higher sensitivity of nuclear Ca ²⁺ stores for InsP ₃ . Nuclear InsP ₃ R channels were active at lower InsP ₃ concentrations than InsP ₃ R from cytosol. Enriched expression of type II InsP ₃ R in the nucleus results in greater sensitivity of the nucleus to InsP ₃ , thus providing a mechanism for independent regulation of Ca ²⁺ -dependent processes in this cellular compartment.

Hepatocyte growth factor (HGF) is important for cell proliferation, differentiation, and related activities. HGF acts through its receptor c-Met, which activates downstream signaling pathways. HGF binds to c-Met at the plasma membrane, where it is generally believed that c-Met signaling is initiated. Here we report that c-Met rapidly translocates to the nucleus upon stimulation with HGF. Ca²⁺ signals that are induced by HGF result from phosphatidylinositol 4,5-bisphosphate hydrolysis and inositol 1,4,5-trisphosphate formation within the nucleus rather than within the cytoplasm. Translocation of c-Met to the nucleus depends upon the adaptor protein Gab1 and importin β1, and formation of Ca²⁺ signals in turn depends upon this translocation. HGF may exert its particular effects on cells because it bypasses signaling pathways in the cytoplasm to directly activate signaling pathways in the nucleus.

Ca²⁺ signals regulate cell proliferation, but the spatial and temporal specificity of these signals is unknown. Here we use selective buffers of nucleoplasmic or cytoplasmic Ca²⁺ to determine that cell proliferation depends upon Ca²⁺ signals within the nucleus rather than in the cytoplasm. Nuclear Ca²⁺ signals stimulate cell growth rather than inhibit apoptosis and specifically permit cells to advance through early prophase. Selective buffering of nuclear but not cytoplasmic Ca²⁺ signals also impairs growth of tumors in vivo. These findings reveal a major physiological and potential pathophysiological role for nucleoplasmic Ca²⁺ signals and suggest that this information can be used to design novel therapeutic strategies to regulate conditions of abnormal cell growth.