Protein O-GlcNAc modulates motility-associated signaling intermediates in neutrophils
Protein O-GlcNAc modulates motility-associated signaling intermediates in neutrophils
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DOI：
10.1074/jbc.m414066200
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发表时间：
2005-04-15
影响因子：
4.8
通讯作者：
Marchase, RB
中科院分区：
文献类型：
--
作者：
Kneass, ZT;Marchase, RB
n -乙酰氨基葡萄糖（O-GlcNAc）对细胞质和核蛋白上丝氨酸/苏氨酸残基的修饰被认为对多种信号转导途径起调节作用。我们之前已经证明，葡萄糖胺（GlcNH(2)）是o - glcn酰化的代谢前体，可以增加o - glcnnac并增强中性粒细胞的运动性。在这里，我们扩展了这种相关性，表明通过抑制O-（2-乙酰氨基-2-脱氧-d -glucopyranosylidene）氨基- n -苯基氨基甲酸酯（PUGNAc）去除O- glcnac的机制不同的方法，增加了由化学引诱剂甲酰基蛋氨酸-赖氨酸-苯丙氨酸（fMLP）诱导的基础细胞运动性和定向迁移。此外，我们证明了O- GlcNAc调节已知的调节中性粒细胞运动的信号中间体的活性。GlcNH(2)和PUGNAc增加了细胞运动的中心介质小GTPase Rac的基础和fmlp诱导的活性。磷酸肌肽3-激酶是Rac活性和中性粒细胞运动的重要调节因子，被证明可以调节GlcNH(2)和PUGNAc作用的信号通路。Rac是中性粒细胞p38和p44/42丝裂原活化蛋白激酶（MAPK）信号传导的重要上游调控元件，这些MAPK参与趋化信号转导。我们发现GlcNH(2)和PUGNAc处理增加了p42/44和p38 MAPK活性，并且这些增加与上游MAPK激酶的激活有关。这些数据表明，o - glcn酰化是中性粒细胞中重要的信号元件，可调节参与细胞运动调节的几种关键信号中间体的活性。
The modification of serine/threonine residues on cytoplasmic and nuclear proteins by N-acetylglucosamine (O-GlcNAc) is suggested to play a role in the regulation of a variety of signal transduction pathways. We have previously shown that glucosamine (GlcNH(2)), a metabolic precursor of O-GlcNAcylation, increases O-GlcNAc and enhances motility in neutrophils. Here, we extend this correlation by showing that a mechanistically distinct means of increasing O-GlcNAc, achieved by inhibition of O-GlcNAc removal with O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc), increases basal cellular motility and directional migration induced by the chemoattractant formyl-methionine-leucine-phenylalanine ( fMLP). Furthermore, we demonstrate that O- GlcNAc modulates the activities of signaling intermediates known to regulate neutrophil movement. GlcNH(2) and PUGNAc increase both the basal and fMLP-induced activity of a central mediator of cellular motility, the small GTPase Rac. Phosphoinositide 3-kinase, an important regulator of Rac activity and neutrophil motility, is shown to regulate the signaling pathway on which GlcNH(2) and PUGNAc act. Rac is an important upstream regulatory element in p38 and p44/42 mitogen-activated protein kinase ( MAPK) signaling in neutrophils, and these MAPKs are implicated in chemotactic signal transduction. We show that GlcNH(2) and PUGNAc treatment increases p42/44 and p38 MAPK activities and that these increases are associated with activation of upstream MAPK kinases. These data indicate that O-GlcNAcylation is an important signaling element in neutrophils that modulates the activities of several critical signaling intermediates involved in the regulation of cellular movement.