Constitutive mutants of the GM-CSF receptor reveal multiple pathways leading to myeloid cell survival, proliferation, and granulocyte-macrophage differentiation
Constitutive mutants of the GM-CSF receptor reveal multiple pathways leading to myeloid cell survival, proliferation, and granulocyte-macrophage differentiation
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DOI：
10.1182/blood-2003-05-1435
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发表时间：
2004-01-15
期刊：
影响因子：
20.3
通讯作者：
Gonda, TJ
中科院分区：
文献类型：
--
作者：
Brown, AL;Peters, M;Gonda, TJ
粒细胞-巨噬细胞集落刺激因子（GM-CSF）受体家族的激活可促进髓细胞室细胞的存活、增殖和分化。几个信号通路在受体的下游被激活，然而尚不清楚这些通路如何诱导特定的生物学结果。我们之前已经发现了人类GM-CSF/ IL-3 /IL-5受体的共享信号亚基人(h) β的2类组成型活性突变体，它们表现出不同的信号传导模式。在一个因子依赖的双电位骨髓细胞系中，FDB1，一个包含跨膜结构域替换的激活突变体（V449E）诱导因子不依赖的增殖和存活，而细胞外结构域的突变体诱导因子不依赖的粒细胞-巨噬细胞分化。在这里，我们使用了进一步的突变分析来证明细胞质域的几个区域在介导增殖、活力和分化方面存在非冗余功能，这在以前的野生型GM-CSF受体研究中没有被揭示。这种独特的冗余缺失揭示了保守的膜近端区域与活力信号的关联，以及酪氨酸577在每一类突变体的活性中至关重要但独特的作用。
Activation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) family of receptors promotes the survival, proliferation, and differentiation of cells of the myeloid compartment. Several signaling pathways are activated downstream of the receptor, however it is not clear how these induce specific biologic outcomes. We have previously identified 2 classes of constitutively active mutants of the shared signaling subunit, human (h) betac, of the human GM-CSF/interieukin-3 (IL-3)/IL-5 receptors that exhibit different modes of signaling. In a factor-dependent bipotential myeloid cell line, FDB1, an activated mutant containing a substitution in the transmembrane domain (V449E) induces factor-independent proliferation and survival, while mutants in the extracellular domain induce factor-independent granulocyte-macrophage differentiation. Here we have used further mutational analysis to demonstrate that there are nonredundant functions for several regions of the cytoplasmic domain with regard to mediating proliferation, viability, and differentiation, which have not been revealed by previous studies with the wild-type GM-CSF receptor. This unique lack of redundancy has revealed an association of a conserved membrane-proximal region with viability signaling and a critical but distinct role for tyrosine 577 in the activities of each class of mutant.