Phosphoinositide Phosphatases

蛋白酪氨酸磷酸酶超家族，它们都包含一个高度保守的活性中心基序Cys- X5-Arg(CX5R)是多种细胞过程的关键调节因子，包括生长、代谢、 分化、运动和细胞程序性死亡。我们的实验室已经证明了一些 含有CX5R基序的磷酸酶利用磷脂酰肌醇而不是磷蛋白作为其 生理底物。这包括肌管蛋白(MTM)亚家族，它可以去除3-磷酸 由磷脂酰肌醇3-磷酸(PI(3)P)和磷脂酰肌醇3，5-二磷酸(PI(3，5)P2)合成。 MTM家族成员的突变被证明是导致人类神经肌肉疾病的原因 肌管性肌病与夏科-玛丽-图斯病(CMT)。这项建议将继续研究 调节MTM家族的PTPs以及另一种新的磷酸酶，称为PTPMT1。在下一个 五年后，我们计划更好地了解PI(3)P的水平如何在细胞内传递信号。 首先，我们将探索MTMR2和MTMR13在一种名为Frabin的新蛋白质中的作用。 PI(3)P水平的变化导致CdC42和其他Rho样蛋白活性的调节 GTP酶。具体地说，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，为隔绝轴突而产生髓鞘的细胞。然后我们将确定这个信号是否 转导通路广泛应用于其他类型的细胞。第二，我们已经证明了PTPMT1 通过减少INS-1细胞中ATP的产生来调节胰岛素的分泌。为了解决PTPMTI的 作用机制方面，我们对PTPMT1基因已被去除的小鼠进行了基因工程。我们是 鉴定这些小鼠的表型，并将结合一系列系统和生化方法 研究PTPMT1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.