Calcineurin/NFAT Signaling Is Required for Neuregulin-Regulated Schwann Cell Differentiation

Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
Science (Impact Factor: 33.61). 02/2009; 323(5914):651-4. DOI: 10.1126/science.1166562
Source: PubMed


Schwann cells develop from multipotent neural crest cells and form myelin sheaths around axons that allow rapid transmission of action potentials. Neuregulin signaling through the ErbB receptor regulates Schwann cell development; however, the downstream pathways are not fully defined. We find that mice lacking calcineurin B1 in the neural crest have defects in Schwann cell differentiation and myelination. Neuregulin addition to Schwann cell precursors initiates an increase in cytoplasmic Ca2+, which activates calcineurin and the downstream transcription factors NFATc3 and c4. Purification of NFAT protein complexes shows that Sox10 is an NFAT nuclear partner and synergizes with NFATc4 to activate Krox20, which regulates genes necessary for myelination. Our studies demonstrate that calcineurin and NFAT are essential for neuregulin and ErbB signaling, neural crest diversification, and differentiation of Schwann cells.

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Available from: Ching-Pin Chang, Oct 17, 2014
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    • "In recent years, studies in mice and humans have revealed unexpected functions for NFATc1 beyond the immune system. In fact, NFATc1 has been linked to cell adaptation and differentiation during embryogenesis, where NFATc1 activation promotes EMT during lineage specification (Kao et al, 2009; Li et al, 2011). We have recently demonstrated ectopic expression and activation of nuclear NFATc1 in the majority of advanced human pancreatic cancers and particularly in cancer cells embedded in inflammatory niches (Buchholz et al, 2006). "

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    • "They upregulate cytokines required for T cell proliferation and stimulate cell growth and differentiation during the T cell response (Kiani et al., 2000). Four of the five known NFAT proteins are part of the T cell response mechanism (Macian, 2005), but NFAT proteins also take part in different regulatory mechanisms of other cells (Crabtree and Olson, 2002; Graef et al., 2001; Hogan et al., 2003; Kao et al., 2009). The C-terminal half of the 930-residue NFAT contains two domains involved in binding DNA and AP-1 and has been characterized structurally (Chen et al., 1998; Jin et al., 2003; Wolfe et al., 1997; Zhou et al., 1998). "
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    ABSTRACT: The serine/threonine phosphatase calcineurin (Cn) targets the nuclear factors of activated T cells (NFATs) that activate cytokine genes. Calcium influx activates Cn to dephosphorylate multiple serine residues within the ∼200 residue NFAT regulatory domain, which triggers joint nuclear translocation of NFAT and Cn. The dephosphorylation process relies on the interaction between Cn and the conserved motifs PxIxIT and LxVP, which are located N- and C-terminal to the phosphorylation sites in NFAT's regulatory domain. Here, we show that an NFATc1-derived 15-residue peptide segment containing the conserved LxVP motif binds to an epitope on Cn's catalytic domain (CnA), which overlaps with the previously established PxIxIT binding site on CnA and is distant to the regulatory domain (CnB). Both NFAT motifs partially compete for binding but do not fully displace each other on the CnA epitope, revealing that both segments bind simultaneously to the same epitope on the catalytic domain.
    Preview · Article · Jun 2014 · Structure
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    • "In addition our enrichment analysis reveals a statistically significant association of PPP3CA with cell differentiation signaling. This result is consistent with the report by Kao et al. that the differentiation of Schwann cells requires the activity of the PPP3CA phosphatase (Kao et al., 2009). Similarly, we found that DUSP26 is significantly correlated with the DNA damage response. "
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    ABSTRACT: Protein phosphorylation homoeostasis is tightly controlled and pathological conditions are caused by subtle alterations of the cell phosphorylation profile. Altered levels of kinase activities have already been associated to specific diseases. Less is known about the impact of phosphatases, the enzymes that down-regulate phosphorylation by removing the phosphate groups. This is partly due to our poor understanding of the phosphatase-substrate network. Much of phosphatase substrate specificity is not based on intrinsic enzyme specificity with the catalytic pocket recognizing the sequence/structure context of the phosphorylated residue. In addition many phosphatase catalytic subunits do not form a stable complex with their substrates. This makes the inference and validation of phosphatase substrates a non-trivial task. Here, we present a novel approach that builds on the observation that much of phosphatase substrate selection is based on the network of physical interactions linking the phosphatase to the substrate. We first used affinity proteomics coupled to quantitative mass spectrometry to saturate the interactome of eight phosphatases whose down regulations was shown to affect the activation of the RAS-PI3K pathway. By integrating information from functional siRNA with protein interaction information, we develop a strategy that aims at inferring phosphatase physiological substrates. Graph analysis is used to identify protein scaffolds that may link the catalytic subunits to their substrates. By this approach we rediscover several previously described phosphatase substrate interactions and characterize two new protein scaffolds that promote the dephosphorylation of PTPN11 and ERK by DUSP18 and DUSP26, respectively.
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