Phosphoinositide Phosphatases

蛋白质酪氨酸磷酸酶超家族，全部含有高度保守的活性位点基序，Cys- X5-Arg (CX5R) 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，一些 含有 CX5R 基序的磷酸酶利用磷酸肌醇而不是磷蛋白作为其 生理基质。这包括去除 3-磷酸盐的肌管蛋白 (MTM) 亚家族 来自磷脂酰肌醇 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会导致人类神经肌肉疾病 肌管肌病和腓骨肌萎缩症 (CMT)。本提案将继续研究 PTP 的 MTM 家族以及另一种称为 PTPMT1 的新型磷酸酶的调节。在接下来的 五年内，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，我们将探讨 MTMR2 和 MTMR13 对于一种名为 Frabin 的新蛋白质的作用。 感知 PI(3)P 水平的变化，从而调节 CDC42 和其他 Rho 样物质的活性 GT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，产生用于绝缘轴突的髓磷脂的细胞。然后我们将确定该信号是否 转导途径广泛应用于其他细胞类型。其次，我们证明了 PTPMT1 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 的问题 作用机制，我们对小鼠进行了基因改造，其中 PTPMT1 基因已被消除。我们是 表征这些小鼠的表型，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.