Abstract
SummaryThe second messenger 3′,5′-cyclic adenosine monophosphate (cAMP) stimulates gene expression via the cAMP-regulated transcriptional coactivator (CRTC) family of cAMP response element-binding protein coactivators. In the basal state, CRTCs are phosphorylated by salt-inducible kinases (SIKs) and sequestered in the cytoplasm by 14-3-3 proteins. cAMP signaling inhibits the SIKs, leading to CRTC dephosphorylation and nuclear translocation. Here we show that although all CRTCs are regulated by SIKs, their interactions with Ser/Thr-specific protein phosphatases are distinct. CRTC1 and CRTC2 associate selectively with the calcium-dependent phosphatase calcineurin, whereas CRTC3 interacts with B55 PP2A holoenzymes via a conserved PP2A-binding region (amino acids 380–401). CRTC3-PP2A complex formation was induced by phosphorylation of CRTC3 at S391, facilitating the subsequent activation of CRTC3 by dephosphorylation at 14-3-3 binding sites. As stimulation of mitogenic pathways promoted S391 phosphorylation via the activation of ERKs and CDKs, our results demonstrate how a ubiquitous phosphatase enables cross talk between growth factor and cAMP signaling pathways at the level of a transcriptional coactivator.
Highlights
The second messenger 30,50-cyclic adenosine monophosphate is a potent driver of cellular responses to hormonal and environmental cues (Montminy, 1997). cAMP mediates the activation of the protein kinase A (PKA) holoenzyme (Taylor et al, 2012), which subsequently phosphorylates cellular substrates (Shabb, 2001)
Selective Binding of Ser/Thr-Specific Protein Phosphatases to cAMP-regulated transcriptional coactivator (CRTC) Family Members they are all regulated by cAMP and the salt-inducible kinases (SIKs), individual CRTC family members can perform unique roles (Figures 1A and 1B)
In previous immunoprecipitation (IP)-mass spectrometry (MS) studies, we identified two conserved SIK/14-3-3-binding sites that inhibit CRTC activity (Sonntag et al, 2017) (S171 and S275 in CRTC2; Figure 1C)
Summary
The second messenger 30,50-cyclic adenosine monophosphate (cAMP) is a potent driver of cellular responses to hormonal and environmental cues (Montminy, 1997). cAMP mediates the activation of the protein kinase A (PKA) holoenzyme (Taylor et al, 2012), which subsequently phosphorylates cellular substrates (Shabb, 2001). CAMP stimulation triggers the PKA-mediated phosphorylation and inhibition of SIK1–3 (Sonntag et al, 2018), leading to the dephosphorylation of CRTCs, which shuttle to the nucleus and drive cAMP/ CREB target gene expression (Wein et al, 2018). In addition to their regulation by SIKs, CRTCs are controlled by calcium signaling via the Ca2+/calmodulin-dependent protein phosphatase calcineurin (CaN) (Perrino et al, 1995), which binds to and dephosphorylates the CRTCs at 14-3-3 binding sites (Altarejos and Montminy, 2011). The most abundant cellular phosphatases protein phosphatase 1 (PP1) and PP2A appear to stimulate the dephosphorylation of CRTC2 (Shi, 2009; Uebi et al, 2010), the context in which these ubiquitous enzymes regulate CRTC activities is unclear
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