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Role of Gab2 and Shp2 in Hematopoietic Signalling

Gab2 和 Shp2 在造血信号传导中的作用

基本信息

批准号：
7842488
负责人：
BENJAMIN G. NEEL
金额：
$ 26.32万
依托单位：
UNIVERSITY HEALTH NETWORK
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-03-15 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7842488
关键词：
1-Phosphatidylinositol 3-Kinase Acute leukemia Address Adult Affect Alleles Binding Proteins Biochemical Biological Biological Assay Bone Marrow Bone Marrow Transplantation Cell Proliferation Cells Cessation of life Child Childhood Chimeric Proteins Chronic Chronic Myeloid Leukemia Complex Cytokine Receptors Data Defect Development Disease Event Funding Genes Genetic Germ Lines Goals Growth Factor Hematological Disease Hematopoiesis Hematopoietic Hemorrhagic Thrombocythemia Human IL3 gene Incidence Induced Mutation Insertional Mutagenesis Juvenile Myelomonocytic Leukemia Knock-in Mouse Link Modeling Molecular Mus Mutation Myelogenous Myeloid Cells Myeloid Metaplasia Myeloproliferative disease Noonan Syndrome Pathogenesis Pathway interactions Phenotype Phosphorylation Play Point Mutation Polycythemia Vera Population Process Proliferating Property Protein Tyrosine Kinase Protein Tyrosine Phosphatase Recruitment Activity Regulation Relative (related person)Reporting Research Research Personnel Risk Role Series Severities Signal Pathway Signal Transduction Src homology 2 domain-containing, transforming protein 1 System Testing Transduction Gene Work cytokine disease phenotype fetal human disease leukemia leukemogenesis loss of function macrophage mast cell mouse model mutant novel novel strategies programs promoter receptor

项目摘要

DESCRIPTION (provided by applicant): Hematopoiesis is regulated by growth factors and cytokines, many of which signal via protein- tyrosine kinases (PTKs). Abnormal PTKs cause myeloproliferative disorders (MPD) and/or leukemia; e.g., leukemia-associated translocations that encode fusion-PTKs (e.g. Bcr/Abl, Tel-Jak2), or point mutations in PTKs, such as the V617F mutation in Jak2 found in many adult MPDs. Protein-tyrosine phosphatases (PTPs) also regulate tyrosyl phosphorylation. Their roles are less well understood, and until recently, PTP mutations had not been identified in MPD/leukemia. The long range goal of this research is to understand the function of the SH2-containing PTP Shp2 (PTPn11) and its binding protein, Gab2, in normal hematopoiesis and disease. Earlier work established that Shp2 in required for cytokine-evoked Ras/Erk pathway activation. More recently, mutations in Shp2, similar to "activated mutants" we generated earlier, were identified in human disease. Germ-line Shp2 mutations cause Noonan syndrome, (NS) an autosomal dominant disorder featuring developmental defects and increased risk of MPD, especially juvenile myelomonocytic leukemia (JMML). Somatic Shp2 mutations are found in JMML and other leukemias. JMML cases without Shp2 mutation have activated Ras or loss-of-function Nf1 mutations, consistent with Shp2's role in regulating Ras, but the biochemical and biological consequences of disease-associated Shp2 mutations was unclear. During the current funding period, we generated and characterized mouse models for NS and JMML. Our results suggested that leukemia-associated Shp2 mutants are strong hypermorphs that cause MPD by enhancing IL3/GMCSF signaling, whereas NS alleles are weaker hypermorphs. However, the extent to which the intrinsic properties of an Shp2 mutation determine disease phenotype, as opposed to genetic modifiers and/or cooperating alleles remains unclear. The target cell in which leukemogenic Shp2 acts remains unidentified, and the precise mechanism by which leukemogenic Shp2 mutants enhance IL3/GMCSF signaling remains unknown. In Preliminary Studies, we have developed a new, unique "knock-in" model for the leukemogenic mutant D61Y and an allelic series of other disease- associated Shp2 knock-in mutants. We will use these models to delineate the effect of leukemogenic and NS mutants, expressed under endogenous promoter control, on hematopoiesis and hematopoietic cell signaling, to identify the target cell(s) for Shp2-evoked MPD, and to assess the relative contribution of disease gene, modifier loci, and secondary events to MPD development. Very recent data indicate that leukemogenic Shp2 mutants act by enhancing Jak2 activation, suggesting a shared molecular pathway between childhood and adult MPD. We also will determine the mechanisms and consequences of Jak2 hyperactivation, and test whether Shp2 mutations may also play a role in adult MPD.

描述(申请人提供)：造血由生长因子和细胞因子调节，其中许多通过蛋白酪氨酸激酶(PTK)传递信号。异常的PTK导致骨髓增殖性疾病(MPD)和/或白血病；例如，编码融合PTK的白血病相关易位(例如BCR/Ab1，TEL-JAK2)，或者PTK的点突变，例如在许多成人MPD中发现的JAK2中的V617F突变。蛋白酪氨酸磷酸酶(PTPs)也调节酪氨酸磷酸化。人们对它们的作用知之甚少，直到最近，在MPD/白血病中还没有发现PTP突变。本研究的长期目标是了解含SH2的PTP Shp2(PTPN11)及其结合蛋白Gab2在正常造血和疾病中的功能。早期的工作证实Shp2是细胞因子诱导的RAS/Erk通路激活所必需的。最近，在人类疾病中发现了Shp2的突变，类似于我们早些时候产生的“激活突变”。胚系Shp2突变导致Noonan综合征(NS)，这是一种常染色体显性遗传病，以发育缺陷和MPD风险增加为特征，尤其是青少年粒单核细胞白血病(JMML)。在JMML和其他白血病中发现了体细胞Shp2突变。没有Shp2突变的JMML患者存在RAS激活或功能丧失的NF1突变，这与Shp2的S在调节RAS中的作用一致，但与疾病相关的Shp2突变的生化和生物学后果尚不清楚。在当前的资助期内，我们为NS和JMML生成了鼠标模型并对其进行了表征。我们的结果表明，白血病相关Shp2突变体是通过增强IL3/GMCSF信号而引起MPD的强超态体，而NS等位基因是弱超态体。然而，Shp2突变的内在属性在多大程度上决定了疾病的表型，而不是遗传修饰物和/或协同作用的等位基因，目前尚不清楚。导致白血病的Shp2作用的靶细胞仍不清楚，导致白血病的Shp2突变体增强IL3/GMCSF信号的确切机制也尚不清楚。在初步研究中，我们为白血病突变D61Y和其他疾病相关Shp2基因突变的等位基因系列开发了一种新的、独特的“敲入”模型。我们将利用这些模型来描述内源性启动子控制下表达的白血病和NS突变体对造血和造血细胞信号的影响，确定Shp2诱导的MPD的靶细胞(S)，并评估疾病基因、修饰基因和次要事件在MPD发生中的相对贡献。最近的数据表明，导致白血病的Shp2突变体通过增强JAK2的激活来发挥作用，这表明儿童和成人MPD之间存在共同的分子途径。我们还将确定JAK2过度激活的机制和后果，并测试Shp2突变是否也可能在成人MPD中发挥作用。