A vitamin D receptor-Ser/Thr phosphatase-p70 S6 kinase complex and modulation of its enzymatic activities by the ligand
A vitamin D receptor-Ser/Thr phosphatase-p70 S6 kinase complex and modulation of its enzymatic activities by the ligand
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DOI：
10.1074/jbc.c200187200
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发表时间：
2002-07-12
影响因子：
4.8
通讯作者：
Nagpal, S
中科院分区：
文献类型：
--
作者：
Bettoun, DJ;Buck, DW;Nagpal, S
我们提供了核受体和Ser/Thr蛋白磷酸酶之间的串扰的证据，并表明维生素D受体（VDR）与蛋白磷酸酶，PP 1c和PP 2Ac的催化亚基相互作用，并以配体依赖的方式诱导其酶活性。PP 1c特异性地与VDR相互作用，但不与酵母中的视黄酸受体a和类维生素A X受体α相互作用。虽然VDR-PP 1c和VDR-PP 2Ac相互作用在体内是不依赖配体的，但1 α，25-二羟基维生素D-3诱导VDR相关磷酸酶活性。此外，VDR对PP 1c/PP 2Ac活性的调节导致其底物p70 S6激酶（p70（S6 k））的快速和特异性去磷酸化和失活。最后，我们证明，内源性VDR，PP 1c或PP 2Ac，和p70（S6 k）是存在于一个三元复合体在体内，和p70（S6 k）与VDR-PP复合物的相互作用是由磷酸化状态的激酶调制。由于p70（S6 k）是G（1）-S转换所必需的，我们的研究结果为1 α，25-二羟维生素D-3诱导结肠癌细胞G（1）阻滞提供了分子基础。
We provide evidence of a cross-talk between nuclear receptor and Ser/Thr protein phosphatases and show that vitamin D receptor (VDR) interacts with the catalytic subunit of protein phosphatases, PP1c and PP2Ac, and induces their enzymatic activity in a ligand-dependent manner. PP1c specifically interacts with VDR but not retinoic acid receptor a and retinoid X receptor alpha in yeast. Although VDR-PP1c and VDR-PP2Ac interaction is ligand-independent in vivo, 1alpha,25-dihydroxy-vitamin D-3 induces VDR-associated phosphatase activity. Further, VDR modulation of PP1c/PP2Ac activity results in a rapid and specific dephosphorylation and inactivation of their substrate, p70 S6 kinase (p70(S6k)). Finally, we demonstrate that the endogenous VDR, PP1c or PP2Ac, and p70(S6k) are present in a ternary complex in vivo, and the interaction of p70(S6k) with the VDR-PP complex is modulated by the phosphorylation state of the kinase. Since p70(S6k) is essential for G(1)-S transition, our results provide a molecular basis of 1alpha,25-dihydroxyvitamin D-3-induced G(1) block in colon cancer cells.