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In eukaryotic cells, calcium entry across the cell surface activates nuclear gene expression, a process critically important for cell growth and differentiation, learning, and memory and immune cell functions. In immune cells, calcium entry occurs through store-operated Ca(2+) release-activated Ca(2+) (CRAC) channels, comprised of STIM1 and Orai1 proteins. Local calcium entry through CRAC channels activates expression of c-fos- and nuclear factor of activated T cells (NFAT)-dependent genes. Although c-fos and NFAT often interact to activate gene expression synergistically, they can be activated independently of one another to regulate distinct genes. This raises the question of how one transcription factor can be activated and not the other when both are stimulated by the same trigger. Here, we show that the lipid raft scaffolding protein caveolin-1 interacts with the STIM1-Orai1 complex to increase channel activity. Phosphorylation of tyrosine 14 on caveolin-1 regulates CRAC channel-evoked c-fos activation without impacting the NFAT pathway or Orai1 activity. Our results reveal that structurally distinct domains of caveolin-1 selectively regulate the ability of local calcium to activate distinct transcription factors. More generally, our findings reveal that modular regulation by a scaffolding protein provides a simple, yet effective, mechanism to tunnel a local signal down a specific pathway.

Original publication




Journal article


Mol Cell Biol

Publication Date





1341 - 1349


Calcium, Calcium Channels, Calcium Signaling, Caveolin 1, Cell Line, Down-Regulation, Gene Expression, HEK293 Cells, Humans, Membrane Proteins, Neoplasm Proteins, ORAI1 Protein, Phosphorylation, Protein Interaction Maps, Protein Structure, Tertiary, Proto-Oncogene Proteins c-fos, STAT5 Transcription Factor, Stromal Interaction Molecule 1, Transcriptional Activation