The Biology of Inositol Polyphosphate Signaling

描述（由申请人提供）：该资助的长期目标是阐明肌醇多磷酸（IP）信号通路，并确定细胞使用它们来引发选择性细胞内反应的机制。我们已经采取了分子的方法来理解这些途径，并已集体克隆和鉴定的IP信使代谢中涉及的许多酶的功能。该提议集中于我们发现的肌醇多磷酸激酶（IPK），其参与将肌醇1，4，5-三磷酸（IP 3）转化为更高的IP信使（如IP 4、IP 5、IP 6和肌醇焦磷酸-PP-IP）。我们对IPKs的研究，在前几年得到了该资助的支持，已经为这些脂质衍生的IP化学密码子在基因表达/转录，mRNA输出，端粒维持，生物体发育的调节中定义了新的信使作用，最近还为肌醇焦磷酸在营养信号传导中的作用。在这项提案中，我们将主要集中在两个激酶，IPMK（也称为IPK 2）和新发现的VIP 1，一种新的IP 6/IP7激酶，另一个IPK参与控制基因表达响应营养变化和细胞形态。我们试图实现两个主要目标：1）阐明IPMK介导的基因表达，生长控制和细胞死亡的控制机制; 2）通过研究令人兴奋的新的进化保守的VIP 1类IP 6/IP7激酶，了解二磷酸肌醇磷酸（也称为肌醇焦磷酸）的作用。总的来说，这项工作将进一步表征IPK依赖的信号通路和解码这些重要细胞调节因子的受体。我们设想IPK调制IP码。通过类比核苷酸代码，我们认为每个IP种类代表一个碱基。到目前为止，已经在细胞中识别出由IPK产生的20多个IP碱基，并且数量还在继续增长。通过改变每个IP碱基的模式和水平，我们认为细胞可以产生能够增强信号特异性的组合复杂的动态代码。我们对IP代码的研究可能会为生物发育，细胞生长控制和与公共卫生相关的营养适应提供新的见解。 公共卫生相关性：我们的建议旨在阐明脂质衍生的磷酸肌醇细胞信号转导途径。调节肌醇磷酸信号传导密码的激酶和磷酸酶的缺陷导致人类疾病和生长控制、适应和生物体发育的缺陷。了解这些必需的酶将为人类细胞生物学提供重要的见解，并通过基础科学研究改善公众健康。

DESCRIPTION (provided by applicant): The long-term goal of this grant is the elucidation of inositol polyphosphate (IP) signaling pathways and determination of the mechanisms by which cells use them to elicit selective intracellular responses. We have taken a molecular approach to understanding these pathways, and have collectively cloned and identified the function of numerous enzymes involved in the metabolism of IP messengers. This proposal focuses on the inositol polyphosphate kinases (IPKs) that we discovered are involved in the conversion of inositol 1,4,5- trisphosphate (IP3) to higher IP messengers (such as IP4, IP5, IP6 and inositol pyrophosphates - PP-IPs). Our studies of the IPKs, supported by this grant in previous years, have led to the definition of novel messenger roles for these lipid-derived IP chemical codes in the regulation of gene expression/transcription, mRNA export, telomere maintenance, organism development and most recently a role for inositol pyrophosphates in nutrient signaling. In this proposal we will focus primarily on two kinases, IPMK (also referred to as IPK2) and the newly discovered VIP1, a novel IP6/IP7 kinase, another IPK implicated in the control of gene expression in response to nutrient change and cell morphology. We seek to accomplish two major objectives: 1) elucidate the mechanisms of IPMK-mediated control of gene expression, growth control and cell death; and 2) understand the roles of diphosphoinositol phosphates, also known as inositol pyrophosphates, through studies of the exciting new evolutionarily conserved VIP1-like class of IP6/IP7 kinase. Overall, this work will further characterize IPK-dependent signaling pathways and the receptors that decode these important cellular regulators. We envision that the IPKs modulate an IP code. By analogy to a nucleotide code, we suggest that each IP species represents a base. Thus far over 20 IP bases generated by IPKs have been identified in cells and the number continues to grow. Through altering the patterns and levels of each IP base, we suggest that a cell may generate a combinatorially complex dynamic code capable of enhancing signaling specificity. Our studies of the IP code will likely provide new insights into organism development, cellular growth control and nutrient adaptation with relevance to public health. Public Health Relevance: Our proposal seeks to elucidate lipid-derived inositol phosphate cellular signal transduction pathways. Defects in the kinases and phosphatases that regulate an inositol phosphate signaling code result in human disease and defects in growth control, adaptation and organism development. Understanding these essential enzymes will provide significant insights into human cell biology and improve public health through basic science research.