Role of protein tyrosine phosphatases in organelle biogenesis

提出的研究计划旨在了解蛋白酪氨酸磷酸酶在吞噬溶酶体（一种模式细胞器）的生物发生中的作用。吞噬溶酶体的生物发生需要多种信号分子的协同作用，包括几种蛋白激酶，它们调节吞噬体与细胞骨架以及早期、晚期和循环内吞室之间的相互作用。最近的一项大规模定量蛋白质组学和磷蛋白质组学分析显示，与全球磷蛋白质组学相比，酪氨酸磷酸化位点在吞噬体中被过度代表。这一发现表明酪氨酸磷酸化在吞噬小体信号传导中起重要作用。适当控制蛋白酪氨酸磷酸化对细胞内稳态至关重要，这是通过蛋白酪氨酸激酶和蛋白酪氨酸磷酸酶的平衡作用来实现的。蛋白酪氨酸磷酸酶在细胞器生物发生中的作用，特别是在吞噬溶酶体生物发生的控制中，很大程度上是未知的。我们的一般假设是蛋白酪氨酸磷酸酶参与吞噬溶酶体的生物发生。为了解决这一假设，我们提出以下目标。

The proposed research program is aimed at understanding the role(s) of protein tyrosine phosphatases in the biogenesis of phagolysosomes, a model organelle. Phagolysosome biogenesis requires the coordinated action of multiple signaling molecules, including several protein kinases, which regulate the interactions between the phagosome and the cytoskeleton, as well as the early, late and recycling endocytic compartments. A recent large scale quantitative proteomic and phosphoproteomic analyses revealed that tyrosine phosphorylation sites are overrepresented in phagosomes, as compared to global phosphoproteome. This finding suggests that tyrosine phosphorylation plays an important role in phagosome signaling. Appropriate control of protein tyrosine phosphorylation is essential for cellular homeostasis, and this is achieved by the balanced action of protein tyrosine kinases and protein tyrosine phosphatases. The role of protein tyrosine phosphatases in organelle biogenesis in general and in the control of phagolysosome biogenesis in particular, is largely unknown. Our general hypothesis is that protein tyrosine phosphatases participate in the biogenesis of phagolysosomes. To address this hypothesis, we propose the following Objectives. 1. To identify and characterize protein tyrosine phosphatases that associate with phagosomes; 2. To determine the role(s) of phagosome-associated protein tyrosine phosphatases in phagolysosome biogenesis; 3. To identify phagosome proteins targeted by protein tyrosine phosphatases using using a proteomic approach. The proposed research program will yield novel information on the regulation of phagolysosome biogenesis, as well as on the role of protein tyrosine phosphatases in this process.