JAK2 ACTIVATION AND CELL-PROLIFERATION INDUCED BY ANTIBODY-MEDIATED PROLACTIN RECEPTOR DIMERIZATION
JAK2 ACTIVATION AND CELL-PROLIFERATION INDUCED BY ANTIBODY-MEDIATED PROLACTIN RECEPTOR DIMERIZATION
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DOI：
10.1210/en.135.4.1299
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发表时间：
1994-10-01
期刊：
影响因子：
4.8
通讯作者：
FARRAR, WL
中科院分区：
文献类型：
--
作者：
RUI, H;LEBRUN, JJ;FARRAR, WL
最近报道了与造血细胞生成素超家族的受体相互作用的细胞因子刺激受体相关的JAK酪氨酸激酶，包括JAK2的PRL活化。与其他酪氨酸激酶不同，JAK激酶迄今为止均未涉及肿瘤发生，并且其参与生长信号传导尚未确定。使用PRL依赖性前T细胞系Nb2，本研究提供了二价二聚化的促红细胞生成素受体和其相关的JAK激酶的激活之间的联系，并证明了一系列二价抗PRL受体抗体的促有丝分裂效力和JAK 2的诱导酪氨酸磷酸化的程度之间的强正相关性。JAK2磷酸化需要抗体二价。单价抗PRL受体Fab片段单独无活性，但其活性可通过与二价抗Fab抗体交联而部分恢复。最有效的受体激动剂单克隆抗体T6的钟形剂量反应曲线提供了抗体诱导受体二聚化的额外证据。当结合的配体分子由于占据而不能邻接第二受体时，这种现象通常在二价配体的药理学浓度下观察到。本研究提供了功能支持的模型PRL受体触发配体诱导的受体同源二聚化和随后激活相关的酪氨酸激酶JAK2。
Cytokines that interact with receptors of the hematopoietin superfamily have recently been reported to stimulate receptor-associated JAK tyrosine kinases, including PRL activation of JAK2. Unlike other tyrosine kinases, none of the JAK kinases has thus far been implicated in oncogenesis, and their involvement in growth signaling has not been established. Using the PRL-dependent pre-T-cell line Nb2, the present study provided a link between bivalent dimerization of a hematopoietin receptor and activation of its associated JAK kinase, and demonstrated a strong positive correlation between the mitogenic potency of a series of bivalent anti-PRL receptor antibodies and the degree of induced tyrosine phosphorylation of JAK2. Antibody bivalency was required for JAK2 phosphorylation. Monovalent anti-PRL receptor Fab fragments alone were inactive, but their activity could be partially restored by cross-linking with bivalent anti-Fab antibodies. Additional evidence for antibody-induced receptor dimerization was provided by a bell-shaped dose-response curve for the most potent receptor agonist, monoclonal antibody T6. This phenomenon is typically seen at pharmacological concentrations of bivalent ligands, when bound ligand molecules fail to adjoin a second receptor due to occupancy. The present study provided functional support for a model of PRL receptor triggering by ligand-induced receptor homodimerization and subsequent activation of the associated tyrosine kinase JAK2.