Tyrosine Dephosphorylation and Blood Cell Development

项目总结 血细胞发育是由环境线索和环境因素之间的动态相互作用来协调的 与生俱来的遗传内容。然而，潜在的细胞内信号机制调节 细胞外信号的造血作用还不是很清楚。这个项目的重点是破译 Shp2在控制造血细胞发育中发挥作用。小鼠Shp2是一种细胞质酪氨酸 最初由申请人克隆的磷酸酶，本实验的主要兴趣是了解 涉及酪氨酸磷酸酶的基本细胞信号机制。已完成的工作 以前的资助周期已经证明Shp2在所有血细胞系的起源中起着关键作用。这 是细胞质酪氨酸磷酸酶促进造血干细胞(HSC)的第一个例子 承诺和差异化。本实验室定义的Shp2在造血中的一般积极作用有 对最近确定显性活性PTPN11/Shp2的因果作用有重要贡献 儿童白血病中的突变，导致PTPN11被鉴定为第一个编码a 酪氨酸磷酸酶。这个相互竞争的更新应用程序的目标是破译 使用条件体细胞基因缺失控制成人正常血细胞发育的Shp2 策略。我们的具体目标是：1)阐明Shp2调节成人HSC自我调节的机制 更新、分化和归巢，以及HSC与生态位的相互作用；2)确定Shp2的作用和 T淋巴细胞发育和功能的机制；3)确定Shp2在B细胞中的作用和机制 淋巴细胞的发育和功能。我们已经产生了新的动物模型和有趣的初步实验 支持这三个目标的数据。这些研究的完成将提供对一般情况的新见解 协调调节HSC活动和细胞指定/发育的机制 造血室里的血统。阐明Shp2在正常造血中的功能也将 导致了一种新的范式，极大地促进了我们对 白血病的发生。

PROJECT SUMMARY Blood cell development is orchestrated by the dynamic interplay between environmental cues and intrinsic genetic contents. However, the intracellular signaling mechanisms underlying regulation of hematopoiesis by extracellular signals are not well understood. The focus of this project is on deciphering Shp2 functions in control of hematopoietic cell development. Murine Shp2 is a cytoplasmic tyrosine phosphatase that was originally cloned by the applicant, and a main interest of this lab is to understand the fundamental cell signaling mechanisms involving tyrosine phosphatases. Work accomplished in the previous funding cycles has demonstrated a pivotal role of Shp2 in genesis of all blood cell lineages. This is the first example that a cytoplasmic tyrosine phosphatase promotes hematopoietic stem cell (HSC) commitment and differentiation. A general positive action of Shp2 in hematopoiesis defined by this lab has contributed significantly to most recent determination of a causal role of dominant active PTPN11/Shp2 mutants in child leukemia, leading to identification of PTPN11 as the first proto-oncogene that encodes a tyrosine phosphatase. The goal of this competing renewal application is to decipher biological functions of Shp2 in control of normal blood cell development in adults, using a conditional somatic gene deletion strategy. Our specific aims are: 1) to elucidate mechanisms by which Shp2 regulates adult HSC self- renewal, differentiation and homing, and also the HSC-niche interaction; 2) to determine Shp2 action and mechanism in T lymphocyte development and functions; 3) to determine Shp2 action and mechanism in B lymphocyte development and functions. We have generated new animal models and interesting preliminary data to support ALL three Aims. Completion of these studies will provide new insights into general mechanisms underlying coordinated regulation of HSC activities and specification/development of cell lineages in the hematopoietic compartment. Elucidation of Shp2 functions in normal hematopoiesis will also lead to a new paradigm that significantly advances our understanding of and fighting against leukemogenesis.