A protein kinase C/Ras/ERK signaling pathway activates myeloid fibronectin receptors by altering β1 integrin sialylation
A protein kinase C/Ras/ERK signaling pathway activates myeloid fibronectin receptors by altering β1 integrin sialylation
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DOI：
10.1074/jbc.m508476200
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发表时间：
2005-11-11
影响因子：
4.8
通讯作者：
Bellis, SL
中科院分区：
文献类型：
--
作者：
Seales, EC;Shaikh, FM;Bellis, SL
在这里，我们报告说，髓样细胞分化沿着单核细胞/巨噬细胞谱系下调ST 6半乳糖-I唾液酸转移酶通过蛋白激酶C/Ras/ERK信号级联。因此，β 1整联蛋白亚基变得低唾液酸化，这刺激α 5 β 1纤连蛋白受体的配体结合活性。蛋白激酶C、Ras和MEK的药理学抑制剂，而不是磷酸肌醇3-激酶，阻断ST 6 Gal-I下调、整合素低唾液酸化和纤连蛋白结合。相反，组成型活性MEK刺激这些相同的事件，这表明ERK是低唾液酸化依赖性整合素激活的必要和充分的激活剂。与低唾液酸化的细胞表面整联蛋白的增强的活性一致，纯化的α 5 β 1受体在酶促去唾液酸化时更强地结合纤连蛋白，这种作用被这些整联蛋白与重组ST 6 Gal-I的再唾液酸化完全逆转。最后，我们绘制了β 1整合素的N-糖基化位点，以更好地了解差异唾液酸化对整合素结构/功能的潜在影响。值得注意的是，在β 1 I样结构域内有三个N-糖基化位点，该区域在配体结合中起关键作用。我们的集体研究结果表明，变异唾液酸化，诱导一个特定的信号级联，介导的持续增加与单核细胞分化相关的细胞凋亡。
Here we report that myeloid cells differentiating along the monocyte/ macrophage lineage down-regulate the ST6Gal-I sialyltransferase via a protein kinase C/Ras/ERK signaling cascade. In consequence, the beta 1 integrin subunit becomes hyposialylated, which stimulates the ligand binding activity of alpha 5 beta 1 fibronectin receptors. Pharmacologic inhibitors of protein kinase C, Ras, and MEK, but not phosphoinositide 3-kinase, block ST6Gal-I down-regulation, integrin hyposialylation, and fibronectin binding. In contrast, constitutively active MEK stimulates these same events, indicating that ERK is both a necessary and sufficient activator of hyposialylation-dependent integrin activation. Consistent with the enhanced activity of hyposialylated cell surface integrins, purified alpha 5 beta 1 receptors bind fibronectin more strongly upon enzymatic desialylation, an effect completely reversed by resialylation of these integrins with recombinant ST6Gal-I. Finally, we have mapped the N-glycosylation sites on the beta 1 integrin to better understand the potential effects of differential sialylation on integrin structure/function. Notably, there are three N-glycosylated sites within the beta 1 I-like domain, a region that plays a crucial role in ligand binding. Our collective results suggest that variant sialylation, induced by a specific signaling cascade, mediates the sustained increase in cell adhesiveness associated with monocytic differentiation.