Granulocyte-macrophage colony-stimulating factor provokes RAS activation and transcription of c-fos through different modes of signaling
Granulocyte-macrophage colony-stimulating factor provokes RAS activation and transcription of c-fos through different modes of signaling
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DOI：
10.1074/jbc.271.13.7587
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发表时间：
1996-03-29
影响因子：
4.8
通讯作者：
Arai, K
中科院分区：
文献类型：
--
作者：
Itoh, T;Muto, A;Arai, K
粒细胞-巨噬细胞集落刺激因子（GM-CSF）可引起靶细胞的增殖反应和早期反应基因如c-fos的诱导，它还诱导细胞蛋白质的快速酪氨酸磷酸化，包括其功能受体的β亚基（β c）。然而，β c内磷酸化酪氨酸残基的位置和功能尚不清楚。为了阐明人GMCSF受体信号转导的机制，使用小鼠BA/F3细胞对β c的胞质结构域进行突变分析。保守的box 1基序的缺失导致β c酪氨酸磷酸化的丧失，从而表明该基序在激活使β c磷酸化的酪氨酸激酶中的重要作用。在位置589处的C-末端截短突变体激活c-fos启动子，并且这种激活通过在酪氨酸577（Tyr（577））处的取代而减弱。然而，在全长β c中的相同取代并没有完全消除c-fos启动子的激活，因此，可能存在冗余的信号通路。当我们分析β c下游的信号分子时，我们发现Tyr（577）对于Shc磷酸化是必需的，而PTP 1D的酪氨酸磷酸化是通过Tyr（577）以及通过其他位点介导的。我们认为，GM-CSF刺激至少两种模式的信号，导致有激活，最终引起启动子激活c-fos的事件。
Granulocyte-macrophage colony-stimulating factor (GM-CSF) provokes a proliferative response and induction of early-response genes such as c-fos in target cells, It also induces rapid tyrosine phosphorylation of cellular proteins, including the beta subunit (beta c) of its functional receptor. However, locations and functions of phosphorylated tyrosine residues within the beta c are unclear, To elucidate the mechanism of the human GMCSF receptor signal transduction, mutational analyses were made of the cytoplasmic domain of the beta c, using murine BA/F3 cells. Deletion of the conserved box 1 motif resulted in loss of tyrosine phosphorylation of the beta c, thereby indicating an essential role for this motif in activating the tyrosine kinase which phosphorylates beta c. A C-terminal truncated mutant at position 589 activated the c-fos promoter, and this activation was diminished by a substitution at tyrosine 577 (Tyr(577)). However, the same substitution in the full-length beta c did not completely abrogate the c-fos promoter activation, hence, redundant signaling pathways probably exist, When we analyzed signaling molecules functioning downstream of the beta c we found that Tyr(577) is essential for Shc phosphorylation, while tyrosine phosphorylation of PTP1D was mediated through Tyr(577) as well as through other site(s). We suggest that GM-CSF stimulates at least two modes of signals leading to has activation, an event which ultimately gives rise to promoter activation of c-fos.