SHP-1/TYK2 INTERACTION AND ITS DEFECT IN FHLH DISEASE

SHP-1/TYK2 相互作用及其在 FHLH 疾病中的缺陷

• 批准号: 6329061
• 负责人: Taolin Yi
• 金额: $ 13.72万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-08 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6329061
• 关键词: JAK kinase; active sites; biological signal transduction; cell growth regulation; cell line; enzyme complex; enzyme deficiency; gene deletion mutation; human tissue; intermolecular interaction; leukemia; neoplasm /cancer genetics; protein tyrosine phosphatase

SHP-1 is an SH-2 domain containing-protein tyrosine phosphatase expressed predominantly in hematopoietic cells. It is a pivotal negative regulator of signaling as demonstrated by the association of SHP-1 deficiency with the murine "motheaten" phenotype, characterized by hyper responsiveness of the motheaten hematopoietic cells to a variety of extracellular stimuli. We and others have shown that SHP-1 functions by associating such membrane receptors through binding of its SH2 domains to specific phosphotyrosine sites in the receptor cytoplasmic region and dephosphorylating key substrates, including the Jak family kinases. Our recent studies demonstrate an intrinsic Jak- binding activity at the N-terminus of the phosphatase and functions independently of the phosphotyrosine binding capacities of the SHP-1 SH2 domains. It may allow SHP-1 recruited to the receptors to specifically target the kinases for dephosphorylation without affecting other phosphotyrosine molecules in the receptor complexes. Since it specifically binds to all Jak family members, we hypothesize that a conserved SHP-1 docking site exists in all Jak kinases and is required for SHP-1 dephosphorylation of the kinases. Importantly, we found that reduced SHP-1 interactions with the Jak family member Tyk2 are associated with the genetically transmitted human luekemic disease familial hemophagocytic lymphohistiocytosis (FHLH). Since SHP-1 appears to be normal in these individuals and that the defect affect only SHP-1 interaction with Tyk2, we hypothesize that a defect in Tyk2 or cellular factors specifically affecting Tyk2 causes reduced SHP- 1/Tyk2 interactions in FHLH and contribute to the pathogenesis of the disease. We propose to 1) define the region in Tyk2 that interacts with SHP-1 and characterize its role in SHP-1 dephosphorylation of the kinase; 2) characterize the molecular defect that causes reduced SHP-l/Tyk2 interactions in FHLH. These studies will make significant contributions toward achieving our long term objective of elucidating the physiological roles of SHP-1 in hematopoietic cells and defining its involvement of hematopoietic diseases.

SHP-1 是一种含有 SH-2 结构域的蛋白酪氨酸磷酸酶 主要表达于造血细胞。 它是一个关键的 信号传导负调节因子的关联表明 具有小鼠“受害”表型的 SHP-1 缺陷，其特征是 通过受损的造血细胞对某种物质的过度反应 各种细胞外刺激。 我们和其他人已经证明 SHP-1 通过结合其膜受体来发挥作用 SH2 结构域连接到受体中特定的磷酸酪氨酸位点 细胞质区域和去磷酸化关键底物，包括 Jak 家族激酶。 我们最近的研究证明了一种内在的 Jak- 磷酸酶 N 末端的结合活性和功能 独立于 SHP-1 SH2 的磷酸酪氨酸结合能力 域。 它可能允许招募到受体上的 SHP-1 特异性地 靶向激酶进行去磷酸化而不影响其他 受体复合物中的磷酸酪氨酸分子。 自从它 与所有 Jak 家族成员特异性结合，我们假设 保守的 SHP-1 对接位点存在于所有 Jak 激酶中并且是必需的 用于激酶的 SHP-1 去磷酸化。 重要的是，我们发现 SHP-1 与 Jak 家族成员 Tyk2 的相互作用减少 与遗传性人类白血病有关 家族性噬血细胞性淋巴组织细胞增多症（FHLH）。自从SHP-1出现以来 在这些个体中是正常的，并且该缺陷仅影响 SHP-1 与 Tyk2 相互作用，我们假设 Tyk2 或细胞中的缺陷 特别影响 Tyk2 的因素会导致 SHP-1/Tyk2 降低 FHLH 中的相互作用并促进该疾病的发病机制。 我们建议 1) 定义 Tyk2 中与 SHP-1 相互作用的区域 表征其在 SHP-1 激酶去磷酸化中的作用； 2） 表征导致 SHP-1/Tyk2 减少的分子缺陷 FHLH 中的相互作用。这些研究将做出重大贡献 以实现我们的长期目标，即阐明 SHP-1在造血细胞中的生理作用及其定义 造血系统疾病的参与。

项目成果

A bipartite NLS at the SHP-1 C-terminus mediates cytokine-induced SHP-1 nuclear localization in cell growth control.

• DOI: 10.1006/bcmd.2002.0485
• 发表时间: 2002
• 期刊: Blood cells, molecules & diseases
• 作者: Wentian Yang;M. Tabrizi;T. Yi

Pentamidine is an inhibitor of PRL phosphatases with anticancer activity.

• 发表时间: 2002-12
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: M. Pathak;D. Dhawan;D. Lindner;E. Borden;C. Farver;T. Yi

The SH2 domain-containing protein tyrosine phosphatase SHP-1 is induced by granulocyte colony-stimulating factor (G-CSF) and modulates signaling from the G-CSF receptor.

含有 SH2 结构域的蛋白酪氨酸磷酸酶 SHP-1 由粒细胞集落刺激因子 (G-CSF) 诱导，并调节来自 G-CSF 受体的信号传导。

• DOI: 10.1038/sj.leu.2401822
• 发表时间: 2000
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Ward,AC;Oomen,SP;Smith,L;Gits,J;vanLeeuwen,D;Soede-Bobok,AA;Erpelinck-Verschueren,CA;Yi,T;Touw,IP
• 通讯作者: Touw,IP