Phosphoinositide Phosphatases

蛋白酪氨酸磷酸酶超家族，所有这些都含有高度保守的活性位点基序，Cys- X5-Arg（CX 5 R）是多种细胞过程的关键介质，包括生长，代谢， 分化、运动和程序性细胞死亡。我们的实验室已经证明， 具有CX 5 R基序的磷酸酶利用磷酸肌醇代替磷蛋白作为其 生理底物这包括去除3-磷酸的肌管蛋白（MTM）亚家族 从磷脂酰肌醇3-磷酸（PI（3）P）和磷脂酰肌醇3，5-二磷酸（PI（3，5）P2. MTM家族成员的突变已被证明是导致人类神经肌肉疾病的原因 肌管性肌病和腓骨肌萎缩症（CMT）。本建议将继续研究 PTPs的MTM家族以及另一种称为PTPMT 1的新型磷酸酶的调节。未来 在接下来的五年里，我们计划更好地了解PI（3）P水平如何在细胞中传输信号。 首先，我们将探索MTMR 2和MTMR 13在一种新蛋白Frabin中的作用， 感觉PI（3）P水平的变化，导致CDC 42和其他Rho样蛋白的活性的调节。 GTP酶。具体来说，我们将研究Frabin在介导PI（3）P信号转导事件中的作用， 雪旺细胞，产生髓鞘以绝缘轴突的细胞。我们将确定这个信号 转导途径广泛用于其他细胞类型。其次，我们已经证明，PTPMT 1 通过减少INS-1细胞中ATP的产生来调节胰岛素分泌。为了解决PTPMTI的 为了研究作用机制，我们对PTPMT 1基因被切除的小鼠进行了基因工程改造。我们 表征这些小鼠的表型，并将联合收割机结合一系列系统和生化方法， 研究PTPMT 1在细胞和整个动物环境中的作用。

The protein tyrosine phosphatase superfamily, all of which contain a highly conserved active site motif, Cys- X5-Arg (CX5R) are key mediators of a wide variety of cellular processes, including growth, metabolism, differentiation, motility, and programmed cell death. Our laboratory has demonstrated that some phosphatases harboring CX5R motifs utilize phosphoinositides instead of phosphoproteins as their physiological substrates. This includes the myotubularin (MTM) subfamily that removes the 3-phosphate from phosphatidylinositol 3-phosphate (PI(3)P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2. Mutations in MTM family members have been shown to cause the human neuromuscular disorders myotubular myopathy and Charcot-Marie-Tooth disease (CMT). This proposal will continue to study the regulation of the MTM family of PTPs as well as another novel phosphatase known as PTPMT1. In the next five years, we plan to develop a better understanding of how levels of PI(3)P transmit signals in the cell. First, we will explore the roles of MTMR2 and MTMR13 with respect to a new protein known as Frabin.which senses changes in PI(3)P levels resulting in the modulation of the activity of CDC42 and other Rho-like GTPases. Specifically, we will examine Frabin's role in mediating PI(3)P signal transduction events in Schwann cells, cells that produce myelin for insulating axons. We will then determine if this signal transduction pathway is widely used in other cell types. Second, we have demonstrated that PTPMT1 regulates insulin secretion by decreasing ATP production in INS-1 cells. In order to address PTPMTI's mechanism of action, we genetically engineered mice in which the PTPMT1 gene has been ablated. We are characterizing these mice phenotypically and will combine a series of systemic and biochemical approaches to study the role of PTPMT1 in cellular and whole animal contexts.