Frederick Joshua P, Mattiske Deidre, Wofford Jessica A, Megosh Louis C, Drake Li Yin, Chiou Shean-Tai, Hogan Brigid L M, York John D
Department of Pharmacology, Howard Hughes Medical Institute, Duke University, Medical Center, Durham, NC 27710, USA.
Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8454-9. doi: 10.1073/pnas.0503706102. Epub 2005 Jun 6.
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.
磷脂酶C和几种肌醇多磷酸激酶（IPK）活性产生了一个分支状的肌醇多磷酸第二信使集合体，这些信使调节细胞核和细胞质中的细胞信号通路。在此，我们报告，Ipk2（也称为肌醇多磷酸多激酶）缺陷的小鼠在胚胎第9.5天左右死亡，伴有多种形态缺陷，包括神经管异常折叠。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物种的合成受到破坏，尽管10%的残余六磷酸肌醇的存在表明存在一条次要的替代途径。纯合突变细胞中存在激动剂诱导的三磷酸肌醇和二磷酸肌醇产生以及钙释放反应，这表明观察到的小鼠表型是未能产生更高阶肌醇多磷酸的结果。我们的数据表明，Ipk2在由1,4,5-三磷酸肌醇衍生的肌醇多磷酸信使的合成中起主要作用，并揭示了它们的产生在胚胎发生和正常发育中的作用。
