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Regulation of Cell proliferation by GM-CSF

GM-CSF 对细胞增殖的调节

基本信息

批准号：
08680678
负责人：
WATANABE Sumiko
金额：
$ 1.34万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08680678/
关键词：
GM-CSF receptor signal trancduction proliferation STAT5 STAT5

项目摘要

Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces various functions including the proliferation and differentiation of a broad rango of hematopoietic cells. We reported that at least two distinct pathways are involved in human GM-CSF receptor signaling both of which require the box 1 region of the common beta (betac) subunit. This region is essential for the activation of JAK2, which is necessary for all the biological functions of GM-CSF.Activation of JAK2 by GM-CSF leads to rapid tyrosine phosphorylation of cellular proteins, including the betac. However, the siguificance of the betac phosphorylation in regards to the regulation of signaling molecules and the expression of GM-CSF function is less well understood. Here we investigated the role of cytoplasmic tyrosine residues of the betac by using a series of betac mutants expressed in murine BA/F3 cells. A mutant betac with all eight cytoplasmic tyrosines converted to phenylalanine (Fall) activated JAK2, but not SHP-2, MAPK cascades, STAT5 or c-fos promoter in BA/F3 cells, nor did it effectively induce proliferation. Adding back each tyrosine to Fall revealed that Tyr577, Tyr612 and Tyr695 are involved in the activation of SHP-2, MAPK cascades and c-fos transcription, while every tyrosine, particularly Tyr612, Tyr695, Tyr750 and Tyr806, facilitated STAT5 activation. Impaired growth was also reatored, at least partly, by any of the tyrosines. These results provide evidence that betac tyrosines possess distinct yet overlapping functions to activate multiple signaling pathways induced by GM-CSF.

粒细胞-巨噬细胞集落刺激因子（GM-CSF）可诱导多种造血细胞的增殖和分化。我们报道了至少两种不同的途径参与人类GM-CSF受体信号传导，这两种途径都需要共同β (β)亚基的box 1区域。该区域对于JAK2的激活至关重要，而JAK2对于GM-CSF的所有生物学功能都是必需的。通过GM-CSF激活JAK2导致细胞蛋白的快速酪氨酸磷酸化，包括β。然而，β - c磷酸化在信号分子调控和GM-CSF功能表达中的意义尚不清楚。本研究通过在小鼠BA/F3细胞中表达的一系列betac突变体，研究了betac细胞质酪氨酸残基的作用。在BA/F3细胞中，8种细胞质酪氨酸全部转化为苯丙氨酸（Fall）的突变β活化了JAK2，但不能激活SHP-2、MAPK级联、STAT5或c-fos启动子，也不能有效诱导增殖。将每个酪氨酸添加回Fall中发现，Tyr577、Tyr612和Tyr695参与了SHP-2、MAPK级联和c-fos转录的激活，而每个酪氨酸，特别是Tyr612、Tyr695、Tyr750和Tyr806，都促进了STAT5的激活。任何一种酪氨酸也至少在一定程度上恢复了受损的增长。这些结果提供了证据，证明β酪氨酸具有不同但重叠的功能，可以激活GM-CSF诱导的多种信号通路。