The role of the inositol polyphosphate 4-phosphatase in cellular signalling

细胞对激素、压力、生长因子和其他环境刺激作出反应，导致分泌、细胞生长、细胞分裂和其他专门功能。这些细胞反应依赖于细胞内信号的产生，这些信号将信息发送到细胞核、细胞骨架或膜区室，从而引起特异性反应。位于膜区室上的信号分子的特定子集被称为磷酸肌醇。我们计划研究一种称为PtdIns（3，4）P2的特定脂质的作用，该脂质将信号蛋白招募到特定的细胞膜，包括细胞内发现的质膜和囊泡的内壁。我们已经确定并正在表征一种称为肌醇多磷酸4-磷酸酶的新型酶，该酶终止PtdIns（3，4）P2产生的信号。我们正在鉴定缺乏这种酶的小鼠。4-磷酸酶缺陷小鼠在脑和骨髓中显示出显著的异常。这些小鼠似乎无法制造循环血小板，这种小的无核细胞对防止出血至关重要。我们将通过检查这些小鼠的骨髓和血液来确定4-磷酸酶在调节血小板生成中的作用。这些研究意义重大，因为血小板生成对于预防创伤后失血至关重要，并且在与血液凝固相关的疾病中也至关重要，包括心脏病发作和中风。其次，我们已经鉴定了一种与4-磷酸酶相关的酶，命名为P-Rex-1，其在脑和神经细胞中高度表达。这项提案旨在确定P-Rex-1是否促进神经发育。

Cells respond to hormones, stress, growth factors and other environmental stimuli resulting in secretion, cell growth, cell division and other specialized functions. These cellular responses are dependent on the generation of intracellular signals that send messages either to the nucleus, the cytoskeleton or membrane compartments and thereby elicit a specific response. A specific subset of signalling molecules that are localized on membrane compartments are called phosphoinositides. We plan to investigate the role of a specific lipid called PtdIns(3,4)P2 that recruits signalling proteins to specific cellular membranes including the inner wall of the plasma membrane and vesicles found within the cell. We have identified and are currently characterizing a novel enzyme called the inositol polyphosphate 4-phosphatase that terminates the signals generated by PtdIns(3,4)P2. We are characterizing mice which lack this enzyme. 4-phosphatase deficient mice demonstrate significant abnormalities in the brain and bone marrow. These mice appear unable to make circulating platelets, small anucleate cells which are vital in preventing bleeding. We will determine how the 4-phosphatase functions in regulating platelet production, by examining the bone marrow and blood of these mice. These studies are significant as platelet production is essential for prevention of blood loss following trauma and also is of vital importance in conditions associated with blood clotting including heart attack and stroke. Secondly we have identified a related enzyme to the 4-phosphatase designated P-Rex-1 which is highly expressed in brain and nerve cells. This proposal aims to determine if P-Rex-1 promotes nerve development.