Activation of p38 has opposing effects on the proliferation and migration of endothelial cells
Activation of p38 has opposing effects on the proliferation and migration of endothelial cells
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DOI：
10.1074/jbc.m407060200
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发表时间：
2005-06-03
影响因子：
4.8
通讯作者：
Pumiglia, KM
中科院分区：
文献类型：
--
作者：
McMullen, ME;Bryant, PW;Pumiglia, KM
病理状况如高血压和高血糖以及球囊血管成形术后的擦伤都会导致内皮功能障碍，从而影响疾病的发病率。这些情况与内皮细胞中多种细胞因子的细化和p38活性的增加有关。然而，p38活性增强与内皮细胞功能之间的关系尚不清楚。为了研究p38 MAPK活性增强对内皮细胞功能的影响，我们表达了p38上游调控因子MEK6的激活突变体（MEK6E）。MEK6E的表达激活了p38，并导致其下游底物热休克蛋白27 （Hsp27）的磷酸化。激活p38不足以诱导细胞凋亡；然而，它确实诱导了p38依赖性细胞周期阻滞。MEK6E的表达足以抑制生长因子和整合素参与引发的ERK磷酸化。MAPK磷酸酶-1 （MKP-1）的表达在p38激活后增加，“底物捕获”MKP-1的表达足以恢复ERK活性。p38的激活足以诱导细胞迁移，这伴随着肌动蛋白结构的改变，其特征是板足增强。缺失所有三个磷酸化位点的突变型Hsp27的共表达，逆转了mek6e诱导的细胞迁移，并改变了p38激活诱导的细胞骨架变化。总的来说，这些结果表明p38活性影响细胞迁移和增殖的决定，p38的长期激活可能导致抗血管生成表型，从而导致内皮功能障碍。
Pathological conditions such as hypertension and hyper-glycemia as well as abrasions following balloon angioplasty all lead to endothelial dysfunction that impacts disease morbidity. These conditions are associated with the elaboration of a variety of cytokines and increases in p38 activity in endothelial cells. However, the relationship between enhanced p38 activity and endothelial cell function remains poorly understood. To investigate the effect of enhanced p38 MAPK activity on endothelial cell function, we expressed an activated mutant of MEK6 (MEK6E), an upstream regulator of p38. Expression of MEK6E activated p38 and resulted in phosphorylation of its downstream substrate, heat shock protein 27 (Hsp27). Activation of p38 was not sufficient to induce apoptosis; however, it did induce p38-dependent cell cycle arrest. MEK6E expression was sufficient to inhibit ERK phosphorylation triggered by growth factors and integrin engagement. MAPK phosphatase-1 (MKP-1) expression was increased upon p38 activation, and expression of a "substrate-trapping" MKP-1 was sufficient to restore ERK activity. Activation of p38 was sufficient to induce cell migration, which was accompanied by alterations in actin architecture characterized by enhanced lamellipodia. Co-expression of a mutant form of Hsp27, lacking all three phosphorylation sites, reversed MEK6E-induced cell migration and altered the cytoskeletal changes induced by p38 activation. Collectively, these results suggest that cellular decisions regarding migration and proliferation are influenced by p38 activity and that prolonged activation of p38 may result in an anti-angiogenic phenotype that contributes to endothelial dysfunction.