LIMES-Institute, Program Unit Development, Genetics and Molecular Physiology, Molecular Developmental Biology, University of Bonn, Carl-Troll-Strasse 31, 53115 Bonn, NRW 53115, Germany.
Center of Advanced European Studies and Research (caesar), Minerva Research Group, Molecular Physiology, Ludwig-Erhard-Allee 2, 53175 Bonn, NRW 53115, Germany.
Dev Cell. 2014 Mar 31;28(6):711-26. doi: 10.1016/j.devcel.2014.02.012.
Calcineurin is a heteromeric Ca(2+)-dependent serine/threonine phosphatase. It dephosphorylates the transcription factor nuclear factor of activated T cells (NFAT) in the cytoplasm, which subsequently undergoes nuclear translocation. NFAT regulates numerous biological processes, including inflammatory T cell responses and cardiac development. Our study identifies the Cysteine-Rich with EGF-Like Domains 1 (Creld1) gene as a regulator of calcineurin/NFATc1 signaling. We show that Creld1 is sufficient to promote NFATc1 dephosphorylation and translocation to the nucleus. Creld1 is contained in a joint protein complex with the regulatory subunit of calcineurin, CnB, thereby controlling calcineurin function. Localization of Creld1 at the endoplasmic reticulum (ER) is important to exert its action on calcineurin. By using Creld1KO mice, we demonstrate that Creld1 is essential for heart development. Creld1 function is required for the VEGF-dependent proliferation of endocardial cells by promoting the expression of NFATc1 target-genes. Collectively, our study identifies Creld1 as an important regulator of calcineurin/NFATc1 signaling.
钙调神经磷酸酶是一种异源三聚体 Ca(2+)-依赖性丝氨酸/苏氨酸磷酸酶。它使细胞质中的活化 T 细胞核因子（NFAT）转录因子去磷酸化，随后发生核转位。NFAT 调节许多生物学过程，包括炎症性 T 细胞反应和心脏发育。我们的研究确定了富含半胱氨酸的表皮生长因子样结构域 1（Creld1）基因是钙调神经磷酸酶/NFATc1 信号的调节剂。我们表明 Creld1 足以促进 NFATc1 的去磷酸化和向核内易位。Creld1 与钙调神经磷酸酶的调节亚基 CnB 一起包含在一个联合蛋白复合物中，从而控制钙调神经磷酸酶的功能。Creld1 在内质网（ER）中的定位对于其对钙调神经磷酸酶的作用很重要。通过使用 Creld1KO 小鼠，我们证明 Creld1 对于心脏发育是必不可少的。Creld1 功能对于内皮细胞中 VEGF 依赖性增殖是必需的，通过促进 NFATc1 靶基因的表达来实现。总之，我们的研究确定 Creld1 是钙调神经磷酸酶/NFATc1 信号的重要调节剂。
