Zhuang H, Patel S V, He T C, Sonsteby S K, Niu Z, Wojchowski D M
Department of Biochemistry, Pennsylvania State University, University Park 16802.
J Biol Chem. 1994 Aug 26;269(34):21411-4.
Receptors for a variety of hematopoietins, interferons alpha/beta and gamma, and growth hormone have recently been shown to mediate rapid, ligand-dependent activation of the Janus-type cytosolic protein-tyrosine kinases Jak1, Jak2, and/or tyk-2. This finding extends relatedness among class I and II cytokine receptors to a functional context and provides an initially satisfying mechanistic analogy to protein-tyrosine kinase-encoding receptors of the epidermal growth factor/platelet-derived growth factor/insulin family. Through the construction and expression of a kinase-deficient form of Jak2 (JK2 delta VIII) in interleukin-3 (IL-3)/erythropoietin (Epo)-dependent DAER cells, we have tested whether activation of Jak2 is required for induced mitogenesis via these class I cytokine receptors. Ectopic expression of JK2 delta VIII inhibited Epo- and IL-3-induced activation of endogenous wild-type Jak2, transiently attenuated IL-3-dependent growth, and essentially abrogated Epo-induced proliferation in this model system. These dominant-negative effects provide the first direct experimental evidence for an essential role for Janus kinase activation in mitogenesis and suggest that distinct effectors may mediate IL-3-induced versus Epo-induced pathways.
最近研究表明，多种造血因子、α/β干扰素、γ干扰素以及生长激素的受体可介导Janus型胞质蛋白酪氨酸激酶Jak1、Jak2和/或tyk-2的快速、配体依赖性激活。这一发现将I类和II类细胞因子受体之间的相关性扩展到了功能层面，并为表皮生长因子/血小板衍生生长因子/胰岛素家族的蛋白酪氨酸激酶编码受体提供了初步令人满意的机制类比。通过在白细胞介素-3（IL-3）/促红细胞生成素（Epo）依赖的DAER细胞中构建并表达Jak2的激酶缺陷形式（JK2δVIII），我们测试了通过这些I类细胞因子受体诱导有丝分裂是否需要Jak2的激活。JK2δVIII的异位表达抑制了Epo和IL-3诱导的内源性野生型Jak2的激活，在该模型系统中短暂减弱了IL-3依赖性生长，并基本消除了Epo诱导的增殖。这些显性负效应为Janus激酶激活在有丝分裂中的重要作用提供了首个直接实验证据，并表明不同的效应器可能介导IL-3诱导的途径与Epo诱导的途径。
