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

SHP-1是一种含有SH-2结构域的蛋白酪氨酸磷酸酶 主要在造血细胞中表达。 这是一个关键的 信号传导的负调节剂，如通过与 SHP-1缺陷伴鼠“蛾化”表型，特征为 通过蛾的造血细胞对一种 各种细胞外刺激。 我们和其他人已经证明，SHP-1 通过结合这些膜受体来发挥功能， SH 2结构域与受体中的特异性磷酸酪氨酸位点 细胞质区域和去磷酸化的关键底物，包括 Jak家族激酶。 我们最近的研究表明，一个内在的杰克- 在磷酸酶的N-末端的结合活性和功能 与SHP-1 SH 2的磷酸酪氨酸结合能力无关 域. 它可能允许SHP-1被募集到受体上， 靶向激酶去磷酸化，而不影响其他 受体复合物中的磷酸酪氨酸分子。 因为它 特异性结合所有Jak家族成员，我们假设 保守的SHP-1对接位点存在于所有的Jak激酶中， 用于SHP-1对激酶的去磷酸化。 重要的是，我们发现， 减少SHP-1与Jak家族成员Tyk 2的相互作用， 与人类遗传性贫血病有关 家族性噬血细胞性淋巴组织细胞增生症（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Tyk 2的相互作用，我们假设Tyk 2或细胞中的缺陷 特异性影响Tyk 2的因素导致SHP- 1/Tyk 2降低 FHLH中的相互作用，并有助于疾病的发病机制。 我们建议：1）定义Tyk 2中与SHP-1相互作用的区域， 表征其在激酶的SHP-1去磷酸化中的作用; 2） 表征导致SHP-1/Tyk 2降低的分子缺陷 FHLH中的相互作用。这些研究将作出重大贡献 为了实现我们的长期目标， SHP-1在造血细胞中的生理作用及其定义 涉及造血系统疾病。

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.