Wöll Stefan, Windoffer Reinhard, Leube Rudolf E
Department of Anatomy and Cell Biology, Johannes Gutenberg University, 55128 Mainz, Germany.
J Cell Biol. 2007 Jun 4;177(5):795-807. doi: 10.1083/jcb.200703174. Epub 2007 May 29.
Plasticity of the resilient keratin intermediate filament cytoskeleton is an important prerequisite for epithelial tissue homeostasis. Here, the contribution of stress-activated p38 MAPK to keratin network organization was examined in cultured cells. It was observed that phosphorylated p38 colocalized with keratin granules that were rapidly formed in response to orthovanadate. The same p38(p) recruitment was noted during mitosis, in various stress situations and in cells producing mutant keratins. In all these situations keratin 8 became phosphorylated on S73, a well-known p38 target site. To demonstrate that p38-dependent keratin phosphorylation determines keratin organization, p38 activity was pharmacologically and genetically modulated: up-regulation induced keratin granule formation, whereas down-regulation prevented keratin filament network disassembly. Furthermore, transient p38 inhibition also inhibited keratin filament precursor formation and mutant keratin granule dissolution. Collectively, the rapid and reversible effects of p38 activity on keratin phosphorylation and organization in diverse physiological, stress, and pathological situations identify p38-dependent signalling as a major intermediate filament-regulating pathway.
弹性角蛋白中间丝细胞骨架的可塑性是上皮组织稳态的重要前提。在此，研究了应激激活的p38丝裂原活化蛋白激酶（MAPK）对培养细胞中角蛋白网络组织的作用。观察到磷酸化的p38与因原钒酸盐而迅速形成的角蛋白颗粒共定位。在有丝分裂期间、各种应激情况下以及产生突变角蛋白的细胞中也观察到相同的p38（p）募集现象。在所有这些情况下，角蛋白8在S73位点发生磷酸化，这是一个众所周知的p38靶位点。为了证明p38依赖性角蛋白磷酸化决定角蛋白组织，通过药理学和遗传学方法调节p38活性：上调诱导角蛋白颗粒形成，而下调则阻止角蛋白丝网络解体。此外，短暂抑制p38也抑制角蛋白丝前体形成和突变角蛋白颗粒溶解。总之，p38活性在不同生理、应激和病理情况下对角蛋白磷酸化和组织的快速且可逆的影响表明，p38依赖性信号传导是调节中间丝的主要途径。
