Tyrosine Dephosphorylation and Blood Cell Development

项目摘要 血细胞的发育是由环境因素和 内在遗传内容然而，细胞内信号转导机制的调节， 通过细胞外信号造血作用还没有被很好地理解。这个项目的重点是破译 Shp 2在控制造血细胞发育中发挥作用。鼠Shp 2是一种细胞质酪氨酸 磷酸酶，最初由申请人克隆，本实验室的主要兴趣是了解 涉及酪氨酸磷酸酶的基本细胞信号传导机制。完成的工作 以前的资助周期已经证明了Shp 2在所有血细胞谱系的发生中的关键作用。这 是细胞质酪氨酸磷酸酶促进造血干细胞（HSC） 承诺和差异化。本实验室定义的Shp 2在造血中的一般积极作用 对最近确定显性活性PTPN 11/Shp 2的因果作用有重要贡献 儿童白血病的突变，导致PTPN 11被鉴定为第一个编码 酪氨酸磷酸酶这一竞争性更新应用的目标是破译 Shp 2在成人正常血细胞发育中的控制，使用条件性体细胞基因缺失 战略我们的具体目标是：1）阐明Shp 2调节成体HSC自我调节的机制， 更新、分化和归巢，以及HSC-生态位相互作用; 2）确定Shp 2作用， 研究Shp 2在B细胞中的作用及其机制 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 数据支持所有三个目标。这些研究的完成将提供新的见解， HSC活性和细胞特化/发育的协调调节机制 造血区室中的谱系。阐明Shp 2在正常造血中的功能也将 导致一种新的范式，大大促进我们对 白血病发生

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.