Thrombopoietin signal transduction requires functional JAK2, not TYK2
Thrombopoietin signal transduction requires functional JAK2, not TYK2
复制标题
DOI：
10.1074/jbc.274.19.13480
复制
发表时间：
1999-05-07
影响因子：
4.8
通讯作者：
Kaushansky, K
中科院分区：
文献类型：
--
作者：
Drachman, JG;Millett, KM;Kaushansky, K
Janus 酪氨酸激酶 (JAK) 家族在细胞因子受体超家族成员的信号转导中发挥着关键作用。为了响应配体-受体相互作用，这些非受体酪氨酸激酶被快速磷酸化和激活，触发酪氨酸磷酸化和下游信号中间体的激活。原癌基因 c-mpl 的产物血小板生成素 (TPO) 与其受体结合后，会激活多种细胞系以及巨核细胞和血小板中的 JAK2 和 TYK2。为了研究这些激酶中的一种或两种对于 TPO 信号转导是否是必需的，我们工程化了亲代人肉瘤细胞系 (2C4) 以及缺乏 JAK2 表达 (gamma 2A) 或 TYK2 表达 (U1A) 的肉瘤细胞系以表达野生型 Mpl 受体。然后检查TPO诱导每个细胞系中Mpl和多种细胞内底物酪氨酸磷酸化的能力。我们的结果表明，JAK2 缺陷细胞 (gamma 2A-Mpl) 无法启动 TPO 介导的信号传导。相反，TYK2 缺陷的细胞 (U1A-Mpl) 能够像亲代细胞 (2C4-Mpl) 一样有效地诱导 Mpl、JAK2、STAT3 和 Shc 的酪氨酸磷酸化。这些数据表明，JAK2 是 Mpl 信号传导的重要组成部分，并且在缺乏 JAK2 的情况下，TYK2 无法启动 TPO 诱导的酪氨酸磷酸化。
The Janus family of tyrosine kinases (JAKs) plays a critical role in signal transduction by members of the cytokine receptor superfamily. In response to ligand-receptor interaction, these nonreceptor tyrosine kinases are rapidly phosphorylated and activated, triggering tyrosine phosphorylation and activation of downstream signaling intermediates. Upon binding to its receptor, the product of the proto-oncogene c-mpl, thrombopoietin (TPO) activates both JAK2 and TYK2 in multiple cell lines as well as megakaryocytes and platelets. To study whether one or both of these kinases are essential for TPO signal transduction, we engineered a parental human sarcoma cell line (2C4) as well as sarcoma cell lines that are deficient in JAK2 expression (gamma 2A) or TYK2 expression (U1A) to express the wild-type Mpl receptor. The ability of TPO to induce tyrosine phosphorylation of Mpl and multiple intracellular substrates in each cell line was then examined. Our results demonstrate that JAK2-deficient cells (gamma 2A-Mpl) are unable to initiate TPO-mediated signaling. In contrast, cells that are TYK2-deficient (U1A-Mpl) are able to induce tyrosine phosphorylation of Mpl, JAK2, STAT3, and Shc as efficiently as parental cells (2C4-Mpl). These data indicate that JAK2 is an essential component of Mpl signaling and that, in the absence of JAK2, TYK2 is incapable of initiating TPO-induced tyrosine phosphorylation.