The GM-CSF receptor utilizes β-catenin and Tcf4 to specify macrophage lineage differentiation.
The GM-CSF receptor utilizes β-catenin and Tcf4 to specify macrophage lineage differentiation.
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DOI：
10.1016/j.diff.2011.08.003
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发表时间：
2012-01
期刊：
影响因子：
2.9
通讯作者：
D'Andrea, Richard J.
中科院分区：
文献类型：
--
作者：
Brown, Anna L.;Salerno, Diana G.;Sadras, Teresa;Engler, Grant A.;Kok, Chung H.;Wilkinson, Christopher R.;Samaraweera, Saumya E.;Sadlon, Timothy J.;Perugini, Michelle;Lewis, Ian D.;Gonda, Thomas J.;D'Andrea, Richard J.
粒细胞巨噬细胞集落刺激因子(GM-CSF)促进正常髓系细胞的生长、存活、分化和活化，是体内全功能巨噬细胞分化所必需的。为了更好地理解生长因子控制增殖和自我更新之间的平衡以及生长抑制和分化之间的平衡的机制，我们使用了双功能FDB1髓样细胞系，它在IL-3中增殖，并在GM-CSF的作用下分化为粒细胞和巨噬细胞。这提供了一个可操作的模型，可以在其中剖析增长和分化之间的转换。我们证明，在GM-CSF受体β亚单位激活突变体的信号背景下，单个细胞内酪氨酸残基(Y577)介导粒细胞命运的决定。在Y577F第二点突变中，粒细胞分化丧失伴随着巨噬细胞分化增强，β-连环蛋白积聚，以及TCF4和其他WNT靶基因的激活。其中包括已知的巨噬细胞系诱导剂Egr1。我们发现，强制表达TCF4或稳定的β-连环蛋白突变体足以促进巨噬细胞对GM-CSF的反应，并且GM-CSF可以调节β-连环蛋白的稳定性，很可能是通过GSK3β。与这一途径在原代细胞中的活性一致，我们表明抑制GSK3CSF活性促进了巨噬细胞集落的形成，而牺牲了粒细胞集落对GM-β的反应。因此，这项研究确定了一条新的途径，通过该途径，生长因子受体信号可以与转录调节因子相互作用，影响髓系分化过程中的谱系选择。
Granulocyte-macrophage colony stimulating factor (GM-CSF) promotes the growth, survival, differentiation and activation of normal myeloid cells and is essential for fully functional macrophage differentiation in vivo. To better understand the mechanisms by which growth factors control the balance between proliferation and self-renewal versus growth-suppression and differentiation we have used the bi-potent FDB1 myeloid cell line, which proliferates in IL-3 and differentiates to granulocytes and macrophages in response to GM-CSF. This provides a manipulable model in which to dissect the switch between growth and differentiation. We show that, in the context of signaling from an activating mutant of the GM-CSF receptor β subunit, a single intracellular tyrosine residue (Y577) mediates the granulocyte fate decision. Loss of granulocyte differentiation in a Y577F second-site mutant is accompanied by enhanced macrophage differentiation, accumulation of β-catenin together with activation of Tcf4 and other Wnt target genes. These include the known macrophage lineage inducer, Egr1. We show that forced expression of Tcf4 or a stabilised β-catenin mutant is sufficient to promote macrophage differentiation in response to GM-CSF and that GM-CSF can regulate β-catenin stability, most likely via GSK3β. Consistent with this pathway being active in primary cells we show that inhibition of GSK3β activity promotes the formation of macrophage colonies at the expense of granulocyte colonies in response to GM-CSF. This study therefore identifies a novel pathway through which growth factor receptor signalling can interact with transcriptional regulators to influence lineage choice during myeloid differentiation.
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DOI：
10.1084/jem.20080759
发表时间：
2008-11-24
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Martinez-Moczygemba M;Doan ML;Elidemir O;Fan LL;Cheung SW;Lei JT;Moore JP;Tavana G;Lewis LR;Zhu Y;Muzny DM;Gibbs RA;Huston DP
通讯作者：
Huston DP
影响因子：
11.4
作者：
Kajiguchi, T.;Chung, E. J.;Trepel, J. B.
通讯作者：
Trepel, J. B.
影响因子：
64.5
作者：
Laslo, Peter;Spooner, Chauncey J.;Singh, Harinder
通讯作者：
Singh, Harinder
影响因子：
8
作者：
Dijkers, PF;van Dijk, TB;Coffer, PJ
通讯作者：
Coffer, PJ
影响因子：
20.3
作者：
Brown, AL;Peters, M;Gonda, TJ
通讯作者：
Gonda, TJ