GSK-3 kinases enhance calcineurin signaling by phosphorylation of RCNs

Abstract

The conserved RCN family of proteins can bind and directly regulate calcineurin, a Ca [Keywords: Calcineurin; calcium signaling; Rcn1p; DSCR1; MCIP; Supplemental material is available at http://www.genesdev.org.

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity

“…However, reduced calcineurin activity is reported to increase worm lifespan, mediated by increased autophagy (Dwivedi et al ., 2009). Studies reporting calcineurin inhibition by RCNs have often been conducted in the context of RCN overexpression, while in the normal range of physiological expression human and yeast RCN can either activate or inhibit calcineurin, depending on context (Hilioti et al ., 2004). This suggests that C. elegans at 25 °C may be in a physiological state where RCAN‐1 activates calcineurin, and rcan‐1 ( RNAi ) knockdown extends lifespan by reducing activity through calcineurin and mTOR.…”

A small molecule‐directed approach to control protein localization and function

“…(D) Schematic illustration of native calcium-responsive signalling pathways (left) and rapamycin-driven Crz1p nuclear localization (right). The results presented here suggest that localization of Crz1p within the nucleus is insufficient to enable target gene expression in the absence of native post-translational modifications and conformational changes conferred by calcium-responsive calcineurin signalling pathways Figure 6B presents a heat map of 68 genes identified as targets of Crz1p in previously published microarray studies (Hilioti et al, 2004;Yoshimoto et al, 2002), including the well-characterized Crz1p targets PMC1, CMK2, GSC2 and RCN1 (Hilioti et al, 2004;Matheos et al, 1997); collectively, the gene set presented here represents the strongest transcriptional profile of Crz1p activity. Upon rapamycin treatment, however, the transcriptional changes observed in these genes are minimal, with only nine genes yielding statistically significant expression changes by significance analysis of microarrays (SAM).…”

“…In response to transitory rises in cytosolic-free Ca 2+ , Crz1p translocates from the cytoplasm to the nucleus through a complex signalling pathway, outlined schematically in Figure 6. In brief, elevated Ca 2+ levels result in activation of the GSK-3 kinase Mck1p, which in turn phosphorylates Rcn1p (Hilioti et al, 2004). Endogenous levels of phosphorylated Rcn1p stimulate calcineurin activity (Hilioti et al, 2004) and calcineurin dephosphorylates Crz1p (StathopoulosGerontides et al, 1999).…”

“…In brief, elevated Ca 2+ levels result in activation of the GSK-3 kinase Mck1p, which in turn phosphorylates Rcn1p (Hilioti et al, 2004). Endogenous levels of phosphorylated Rcn1p stimulate calcineurin activity (Hilioti et al, 2004) and calcineurin dephosphorylates Crz1p (StathopoulosGerontides et al, 1999). Crz1p activity is further modulated by the response-regulator transcription factor Skn7p, which binds to both calcineurin and Crz1p, protecting Crz1p from degradation (Williams and Cyert, 2001).…”

“…Yeast cells were treated with rapamycin or a solvent control, and RNA was extracted at 0, 15, 30 and 60 min post-treatment. Previous microarray studies of Crz1p-mediated transcriptional activation were used to define the target gene set presented here; in particular, genes identified by both Yoshimoto et al (2002) and Hilioti et al (2004) as Crz1p-targets are shown, along with genes from either dataset exhibiting significant expression changes in our analysis. SAM scores >1.0 indicate significant expression changes; only nine genes exhibited changes exceeding this confidence level, yielding a transcriptional profile distinct from that observed during wild-type activation of Crz1p.…”