DISTINCT REGIONS OF C-MPL CYTOPLASMIC DOMAIN ARE COUPLED TO THE JAK-STAT SIGNAL-TRANSDUCTION PATHWAY AND SHC PHOSPHORYLATION
DISTINCT REGIONS OF C-MPL CYTOPLASMIC DOMAIN ARE COUPLED TO THE JAK-STAT SIGNAL-TRANSDUCTION PATHWAY AND SHC PHOSPHORYLATION
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DOI：
10.1073/pnas.92.12.5292
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发表时间：
1995-06-06
影响因子：
11.1
通讯作者：
DESAUVAGE, FJ
中科院分区：
文献类型：
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作者：
GURNEY, AL;WONG, SC;DESAUVAGE, FJ
c-Mpl是造血细胞因子受体家族的一员，是血小板生成素的受体。为了研究c-Mpl的信号转导作用，将一种由生长激素受体胞外结构域和c-Mpl胞内结构域组成的嵌合受体引入白细胞介素3依赖性细胞系Ba/F3。作为对生长激素的反应，这种嵌合受体在缺乏白细胞介素3的情况下诱导生长。123个氨基酸的胞内结构域的缺失分析表明，负责这种作用的元件存在于跨膜结构域附近的63个氨基酸中，最近描述的box 1基序突变取消了增殖反应，酪氨酸激酶JAK-2的酪氨酸磷酸化和STAT蛋白的激活依赖于box 1和质膜上63个氨基酸的序列。在巨核细胞系中纯化了由血小板生成素激活的STAT蛋白，结果显示为STAT1和STAT3。位于C - mpl胞内结构域C端的一个单独区域被发现是诱导Shc磷酸化和C -fos mRNA积累所必需的，这表明Ras信号转导通路参与其中。因此，至少有两个不同的区域参与c-Mpl的信号转导。
c-Mpl, a member of the hematopoietic cytokine receptor family, is the receptor for thrombopoietin. To investigate signal transduction by c-Mpl, a chimeric receptor, composed of the extracellular domain of human growth hormone receptor and the intracellular domain of c-Mpl, was introduced into the interleukin 3-dependent cell line Ba/F3. In response to growth hormone, this chimeric receptor induced growth in the absence of interleukin 3. Deletion analysis of the 123-amino acid intracellular domain indicated that the elements responsible for this effect are present within the 63 amino acids proximal to the transmembrane domain, Mutation of the recently described box 1 motif abrogated the proliferative response, Tyrosine phosphorylation of the tyrosine kinase JAK-2 and activation of STAT proteins were dependent on box 1 and sequences within 63 amino acids of the plasma membrane. STAT proteins activated by thrombopoietin in a megakaryocytic cell line were purified and shown to be STAT1 and STAT3. A separate region located at the C terminus of the c-Mpl intracellular domain nas found to be required for induction of Shc phosphorylation and c-fos mRNA accumulation, suggesting involvement of the Ras signal transduction pathway. Thus, at least two distinct regions are involved in signal transduction by the c-Mpl.