Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
J Cell Biol. 2013 May 27;201(5):681-92. doi: 10.1083/jcb.201208162. Epub 2013 May 20.
Maintenance of epithelial cell adhesion is crucial for epidermal morphogenesis and homeostasis and relies predominantly on the interaction of keratins with desmosomes. Although the importance of desmosomes to epidermal coherence and keratin organization is well established, the significance of keratins in desmosome organization has not been fully resolved. Here, we report that keratinocytes lacking all keratins show elevated, PKC-α-mediated desmoplakin phosphorylation and subsequent destabilization of desmosomes. We find that PKC-α activity is regulated by Rack1-keratin interaction. Without keratins, desmosomes assemble but are endocytosed at accelerated rates, rendering epithelial sheets highly susceptible to mechanical stress. Re-expression of the keratin pair K5/14, inhibition of PKC-α activity, or blocking of endocytosis reconstituted both desmosome localization at the plasma membrane and epithelial adhesion. Our findings identify a hitherto unknown mechanism by which keratins control intercellular adhesion, with potential implications for tumor invasion and keratinopathies, settings in which diminished cell adhesion facilitates tissue fragility and neoplastic growth.
维持上皮细胞黏附对于表皮形态发生和稳态至关重要，主要依赖于角蛋白与桥粒之间的相互作用。尽管桥粒对于表皮的连贯性和角蛋白组织的重要性已得到充分证实，但角蛋白在桥粒组织中的意义尚未完全解决。在这里，我们报告说，缺乏所有角蛋白的角质形成细胞显示出升高的、PKC-α 介导的桥粒斑蛋白磷酸化，随后桥粒不稳定。我们发现 PKC-α 活性受到 Rack1-角蛋白相互作用的调节。没有角蛋白，桥粒会组装，但内吞作用的速度会加快，使上皮片对机械应力非常敏感。角蛋白对 K5/14 的重新表达、PKC-α 活性的抑制或内吞作用的阻断都重建了质膜上的桥粒定位和上皮黏附。我们的发现确定了一个迄今为止未知的机制，即角蛋白控制细胞间黏附，这可能对肿瘤侵袭和角蛋白病有影响，在这些情况下，细胞黏附的减少会导致组织脆弱和肿瘤生长。
