Characterization of 72 and 52 kDa inositol polyphosphate 5-phosphatases: role in vesicular trafficking and cell death

细胞对外部环境、压力、激素和生长因子的反应是在细胞内部产生信息，向细胞核发送刺激细胞生长的信号。一个这样的信号网络是由称为磷脂酰肌醇的膜脂产生的。修饰这些膜脂的酶或激酶，特别是一种被称为PI3-激酶的酶，会产生强大的信号分子来调节细胞生长。许多研究表明，在某些人类癌症中，PI 3-激酶产生的信号会被放大。遗传性癌症综合征已被描述为细胞失去了关闭这些脂质信使分子的能力。目前的项目旨在研究最近发现的两种被称为5-磷酸酶的酶，它们具有终止PI3-激酶膜信号的能力。这两种酶都是由宿主实验室分离并鉴定的，预计它们将在细胞中发挥不同的作用。据预测，72 kDa的5-磷酸酶调节蛋白质和囊泡到细胞表面的运输。这项建议旨在研究72 kDa 5-磷酸酶是否可以调节细胞内新蛋白质的细胞内分选。我们还注意到，72 kDa的5-磷酸酶可能在神经系统的发育中发挥作用，特别是神经发出分支和分化的能力。这项提案将对这一假设进行调查。我们分离的第二个酶是一个52 kDa的5-磷酸酶。这种酶存在于许多细胞中。我们有令人信服的证据表明，这种酶与最近分离的一种名为SODD的蛋白质形成了一种复合体，这种蛋白质可以阻止细胞对不适当的信号做出反应而死亡。我们预测52 kDa的5-磷酸酶可能像在癌症中观察到的那样，起到阻止延长细胞存活的作用。我们将研究这种酶是否调节细胞死亡途径，以及52 kDa 5-磷酸酶水平的增加或减少是否会改变细胞的存活

Cells respond to the external environment, stress, hormones and grow th factors by generating messages inside the cell that send a signal to the nucleus that stimulates cell growth. One such signalling network is that produced by membrane lipids known as phosphoinositides. Enzymes or kinases that modify these membrane lipids in particular an enzyme known as the PI 3-kinase generate potent signalling molecules that regulate cell growth. It has been shown by many studies that signals generated by the PI 3-kinase are amplified in certain human cancers. Inherited cancer syndromes have been described in which the cell has lost the ability to switch off these lipid messenger molecules. The current project aims to investigate two recently identified enzymes called 5-phosphases that have the ability to terminate PI 3-kinase membrane signals. Both these enzymes were isolated and characterized by the host laboratory and it is predicted they will play distinct roles in the cell. The 72 kDa 5-phosphatase is predicted to regulate protein and vesicular trafficking to the surface of cell. This proposal aims to investigate if the 72 kDa 5-phosphatase can regulate the intracellular sorting of new proteins within the cell. We have also noted the 72 kDa 5-phosphatase may play a role in the development of the nervous system in particular the ability of nerves to send branches out and differentiate. This proposal will investigate this hypothesis. The second enzyme that we have isolated is a 52 kDa 5-phosphatase. This enzyme is present in many cells. We have compelling evidence that the enzyme forms a complex with a recently decribed protein called SODD that stops cells from dying in response to inappropropirate signals. We predict the 52 kDa 5-phosphatase may function to prevent prolonged cell survival as is observed in cancer. We will investigate if this enzyme regulates the cell death pathway and if increased or decreased levels of the 52 kDa 5-phosphatase alter cell survival