The Biology of Inositol Polyphosphate Signaling

描述(由申请人提供)：这项资助的长期目标是阐明肌醇多磷酸(IP)信号通路，并确定细胞利用它们来引发选择性细胞内反应的机制。我们采取了分子方法来了解这些途径，并共同克隆和鉴定了参与IP信使代谢的许多酶的功能。本研究的重点是我们发现的参与肌醇1，4，5-三磷酸(IP3)向更高IP信使(如IP4、IP5、IP6和肌醇焦磷酸盐-PP-IPs)转化的肌醇多聚磷酸酶(IPK)。在前些年的资助下，我们对IPK的研究已经确定了这些脂类衍生的IP化学密码在基因表达/转录调控、mRNA输出、端粒维持、生物体发育中的新信使角色，以及最近肌醇焦磷酸在营养信号中的作用。在这项提案中，我们将主要关注两个激酶，IPMK(也称为IPK2)和新发现的VIP1，一种新的IP6/IP7激酶，另一种参与调控基因表达的IPK，以响应营养变化和细胞形态。我们试图完成两个主要目标：1)阐明IPMK介导的基因表达、生长控制和细胞死亡的调控机制；2)通过研究令人兴奋的、进化上保守的新的类VIP1的IP6/IP7激酶，了解二磷酸肌醇磷酸盐(又称肌醇焦磷酸盐)的作用。总体而言，这项工作将进一步表征依赖IPK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代码。通过类似于核苷酸代码，我们认为每个IP物种代表一个碱基。到目前为止，已在细胞中鉴定出20多个由IPK产生的IP碱基，而且这个数字还在继续增长。通过改变每个IP碱基的模式和水平，我们认为一个细胞可以产生一个组合复杂的动态代码，能够增强信号的特异性。我们对IP代码的研究可能会为生物体发育、细胞生长控制和与公共健康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肌醇磷酸肌醇细胞信号转导途径。调节肌醇磷酸信号密码的激酶和磷酸酶的缺陷会导致人类疾病，并导致生长控制、适应和生物体发育的缺陷。了解这些关键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.