Abstract
SummaryProtein isoforms are widely expressed in biological systems. How isoforms that co-exist within the same sub-cellular domain are differentially activated remains unclear. Here, we compare the regulatory mechanism of two closely related transcription factor isoforms, NFAT1 and NFAT4, that migrate from the cytoplasm to the nucleus following the increase in intracellular Ca2+ that accompanies the opening of store-operated Orai1/CRAC channels. We demonstrate that NFAT1 has a private line of communication with Orai1, activating in response to Ca2+ microdomains near the open channels. By contrast, NFAT4 stimulation requires both local Ca2+ entry and a nuclear Ca2+ rise. We mapped differences in nuclear location to amino acids within the SP-3 motif of the NFAT regulatory domain. The different Ca2+ dependencies enable agonists to recruit different isoform combinations as stimulus strength increases. Our study uncovers a mechanism whereby co-existing cytoplasmic transcription factor isoforms are differentially activated by distinct sub-cellular Ca2+ signals.
Highlights
Many signaling proteins have multiple isoforms that are often co-expressed in the same cell
Upon stimulation with agonists that increase intracellular Ca2+, these transcription factors are dephosphorylated by Ca2+-calmodulin activated protein phosphatase calcineurin, which exposes a nuclear localization sequence and enables the protein to translocate to the nucleus where it regulates gene expression (Muller and Rao, 2010; Wu et al, 2007)
NFAT1 and NFAT4 are often co-expressed in cells, occupy the same cytoplasmic location, and are activated by intracellular Ca2+
Summary
Many signaling proteins have multiple isoforms that are often co-expressed in the same cell. Critical questions are how some isoforms can be activated, but not others, when they are co-expressed and how different isoforms evoke distinct effects. This issue is nicely encapsulated by the NFAT family of transcription factors, which are essential for vertebrate development, differentiation, and function. Four members of the NFAT family (NFAT1–4) are activated by cytoplasmic Ca2+ and are encoded by highly homologous genes (Hogan et al, 2003). Upon stimulation with agonists that increase intracellular Ca2+, these transcription factors are dephosphorylated by Ca2+-calmodulin activated protein phosphatase calcineurin, which exposes a nuclear localization sequence and enables the protein to translocate to the nucleus where it regulates gene expression (Muller and Rao, 2010; Wu et al, 2007)
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