Identification of a novel agrin-dependent pathway in cell signaling and adhesion within the erythroid niche
Identification of a novel agrin-dependent pathway in cell signaling and adhesion within the erythroid niche
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DOI：
10.1038/cdd.2016.10
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发表时间：
2016-08-01
影响因子：
12.4
通讯作者：
Viola, A.
中科院分区：
文献类型：
--
作者：
Anselmo, A.;Lauranzano, E.;Viola, A.
细胞-细胞粘附的建立在胚胎发育中以及在成人的干细胞龛内是至关重要的。巨噬细胞和成红细胞之间的粘附是形成成红细胞岛所必需的，成红细胞岛是成红细胞在整个生命过程中增殖和分化以产生红细胞的特化小生境。Eph家族是已知的最大的受体酪氨酸激酶（RTK）家族，并且通过调节整联蛋白和粘附分子活性以及通过修饰肌动蛋白细胞骨架来控制细胞粘附、迁移、侵袭和形态。在这里，我们确定了蛋白聚糖聚集蛋白作为一种新的调节Eph受体信号和表征一种新的机制控制细胞间粘附和红细胞发育的红细胞龛内。我们证明聚集蛋白诱导EphB 1受体在发育中的成红细胞上的聚集和激活，导致α 5 β 1整合素的激活。与此一致，聚集蛋白基因敲除小鼠由于与巨噬细胞的粘附缺陷和红系细胞成熟受损而表现出严重的贫血。这些结果将聚集蛋白-EphB 1定位为调节细胞粘附和红细胞生成的新型关键信号传导对。
Establishment of cell-cell adhesion is crucial in embryonic development as well as within the stem cell niches of an adult. Adhesion between macrophages and erythroblasts is required for the formation of erythroblastic islands, specialized niches where erythroblasts proliferate and differentiate to produce red blood cells throughout life. The Eph family is the largest known family of receptor tyrosine kinases (RTKs) and controls cell adhesion, migration, invasion and morphology by modulating integrin and adhesion molecule activity and by modifying the actin cytoskeleton. Here, we identify the proteoglycan agrin as a novel regulator of Eph receptor signaling and characterize a novel mechanism controlling cell-cell adhesion and red cell development within the erythroid niche. We demonstrate that agrin induces clustering and activation of EphB1 receptors on developing erythroblasts, leading to the activation of alpha 5 beta 1 integrins. In agreement, agrin knockout mice display severe anemia owing to defective adhesion to macrophages and impaired maturation of erythroid cells. These results position agrin-EphB1 as a novel key signaling couple regulating cell adhesion and erythropoiesis.