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

SHP-1是一个含SH-2结构域的蛋白酪氨酸磷酸酶 主要在造血细胞中表达。它是一个关键的 信号的负调节因子，如联合 SHP-1缺乏症伴小鼠“Motheten”表型，特征为 由于母系造血细胞对一种 各种细胞外刺激。我们和其他人已经证明了SHP-1 通过结合其受体来结合这种膜受体的功能 受体中特定的磷酸酪氨酸位点的Sh2结构域 细胞质区域和去磷酸化的关键底物，包括 杰克家族的血缘关系。我们最近的研究证明了一种内在的雅克- 磷酸酶N末端的结合活性及其功能 不依赖于SHP-1 SH2的磷酸酪氨酸结合能力 域名。它可能允许招募到受体的SHP-1特异性地 靶向去磷酸化的激酶而不影响其他 受体复合体中的磷酸酪氨酸分子。因为它 明确绑定到所有Jak家族成员，我们假设一个 保守的SHP-1对接位点存在于所有JAK激酶中，是必需的 用于SHP-1去磷酸化的激酶。重要的是，我们发现 减少了SHP-1与JAK家族成员TYK2的相互作用 与通过基因传播的人类狼疮有关 家族性噬血细胞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，并且缺陷只影响SHP-1 与TYK2的相互作用，我们假设TYK2或细胞中的缺陷 特定影响TYK2的因素导致SHP-1/TYK2降低 FHLH中的相互作用，并在疾病的发病机制中起作用。 我们建议1)定义TYK2中与SHP-1相互作用的区域，并 鉴定其在SHP-1去磷酸化该激酶中的作用；2) 表征导致SHP-L/TYK2降低的分子缺陷 FHLH中的相互作用。这些研究将做出重大贡献。 为了达到我们的长期目标，即澄清 SHP-1在造血细胞中的生理作用及其定位 血液病的累及。

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.