Essential role of protein kinase C ζ in transducing a motility signal induced by superoxide and a chemotactic peptide, fMLP
Essential role of protein kinase C ζ in transducing a motility signal induced by superoxide and a chemotactic peptide, fMLP
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DOI：
10.1083/jcb.200607019
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发表时间：
2007-03-01
影响因子：
7.8
通讯作者：
Niitsu, Yoshiro
中科院分区：
文献类型：
--
作者：
Kuribayashi, Kageaki;Nakamura, Kiminori;Niitsu, Yoshiro
在各种病理条件下，包括感染、恶性肿瘤和自身免疫性疾病，组织不断暴露于由浸润的炎性细胞产生的活性氧。我们发现，超氧化物刺激与人鳞状细胞癌SASH 1细胞，人外周血单核细胞（hPMs）和小鼠巨噬细胞样细胞系J774.1的形态学变化相关的运动增强。我们还公开了由趋化肽（N-甲酰基-甲硫氨酰亮氨酰-苯丙氨酸[fMLP]）诱导的hPMs和J774.1的运动性被超氧化物歧化酶或N-乙酰半胱氨酸抑制，表明由fMLP刺激产生的超氧化物对运动性的刺激。在这些细胞中，蛋白激酶C（PKC）zeta被激活以磷酸化RhoGDI-1，其释放RhoGTP酶，导致其激活。这些事件被SASH 1细胞中的显性负性PKC zeta、hPM和J774.1中的肉豆蔻酰化PKC zeta肽或SASH 1、hPM和J774.1中的RhoGTT的特异性抑制剂抑制。这些结果提示了一种通过靶向这种新的信号通路来操纵炎症以及肿瘤细胞侵袭的新方法。
Under various pathological conditions, including infection, malignancy, and autoimmune diseases, tissues are incessantly exposed to reactive oxygen species produced by infiltrating inflammatory cells. We show augmentation of motility associated with morphological changes of human squamous carcinoma SASH1 cells, human peripheral monocytes (hPMs), and murine macrophage-like cell line J774.1 by superoxide stimulation. We also disclose that motility of hPMs and J774.1 induced by a chemotactic peptide (N-formyl-methionylleucyl-phenylalanine [fMLP]) was inhibited by superoxide dismutase or N-acetylcystein, indicating stimulation of motility by superoxide generated by fMLP stimulation. In these cells, protein kinase C (PKC) zeta was activated to phosphorylate RhoGDI-1, which liberated RhoGTPases, leading to their activation. These events were inhibited by dominant-negative PKC zeta in SASH1 cells, myristoylated PKC zeta peptides in hPMs and J774.1, or a specific inhibitor of RhoGTPase in SASH1, hPMs, and J774.1. These results suggest a new approach for manipulation of inflammation as well as tumor cell invasion by targeting this novel signaling pathway.