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、细胞分裂等特殊功能。这些细胞反应依赖于细胞内信号的产生，这些信号向细胞核、细胞骨架或膜间隔发送信息，从而引发特定的反应。定位在膜上的信号分子的一个特定子集被称为磷脂酰肌醇。我们计划研究一种名为PtdIns(3，4)P2的特定脂质的作用，它将信号蛋白招募到特定的细胞膜上，包括质膜的内壁和细胞内发现的小泡。我们已经鉴定了一种新的酶，称为肌醇多磷酸4-磷酸酶，它能终止PtdIns(3，4)P2产生的信号。我们正在刻画缺乏这种酶的老鼠的特征。4-磷酸酶缺乏的小鼠在大脑和骨髓中表现出显著的异常。这些小鼠似乎不能产生循环的血小板，这是一种对防止出血至关重要的小无核细胞。我们将通过检查这些小鼠的骨髓和血液来确定4-磷酸酶如何调节血小板的产生。这些研究意义重大，因为血小板的产生对于预防创伤后的失血至关重要，对心脏病发作和中风等与血液凝结相关的情况也是至关重要的。其次，我们鉴定了一种与4-磷酸酶相关的酶，命名为P-Rex-1，它在大脑和神经细胞中高表达。这项提议旨在确定P-霸王龙-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.