An essential role for an inositol polyphosphate multikinase, Ipk2, in mouse embryogenesis and second messenger production
An essential role for an inositol polyphosphate multikinase, Ipk2, in mouse embryogenesis and second messenger production
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DOI：
10.1073/pnas.0503706102
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发表时间：
2005-06-14
影响因子：
11.1
通讯作者：
York, JD
中科院分区：
文献类型：
--
作者：
Frederick, JP;Mattiske, D;York, JD
磷脂酶C和几种肌醇多磷酸激酶（IPK）活性产生肌醇多磷酸第二信使的分支集合，调节细胞核和细胞质中的细胞信号通路。在这里，我们报道Ipk2（也被称为肌醇多磷酸激酶）缺乏的小鼠在胚胎9.5天左右死亡，并伴有多种形态缺陷，包括神经管异常折叠。Ipk2是一种肌醇三磷酸和四磷酸6/5/3激酶，在肌醇代谢途径的几个地方活跃。ipk2缺陷细胞的代谢分析表明，大多数五磷酸肌醇、六磷酸肌醇和焦磷酸肌醇的合成被破坏，尽管10%的六磷酸肌醇残留表明存在少量替代途径。纯合子突变细胞中存在激动剂诱导的肌醇三磷酸和二磷酸产生和钙释放反应，表明观察到的小鼠表型是无法产生高肌醇多磷酸的结果。我们的数据表明，Ipk2在肌醇1,4,5-三磷酸衍生的肌醇多磷酸信使的合成中起主要作用，并揭示了它们在胚胎发生和正常发育中的作用。
Phospholipase C and several inositol polyphosphate kinase (IPK) activities generate a branched ensemble of inositol polyphosphate second messengers that regulate cellular signaling pathways in the nucleus and cytoplasm. Here, we report that mice deficient for Ipk2 (also known as inositol polyphosphate multikinase), an inositol trisphosphate and tetrakisphosphate 6/5/3-kinase active at several places in the inositol metabolic pathways, die around embryonic day 9.5 with multiple morphological defects, including abnormal folding of the neural tube. Metabolic analysis of Ipk2-deficient cells demonstrates that synthesis of the majority of inositol pentakisphosphate, hexakisphosphate and pyrophosphate species are disrupted, although the presence of 10% residual inositol hexakisphosphate indicates the existence of a minor alternative pathway. Agonist induced inositol tris- and bis-phosphate production and calcium release responses are present in homozygous mutant cells, indicating that the observed mouse phenotypes are a result of failure to produce higher inositol polyphosphates. Our data demonstrate that Ipk2 plays a major role in the synthesis of inositol polyphosphate messengers derived from inositol 1,4,5-trisphosphate and uncovers a role for their production in embryogenesis and normal development.