Department of Orthodontics, Center for Dental Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany; Faculty of Engineering, University of Freiburg, Georges-Köhler-Allee 101, 79110 Freiburg, Germany.
Division of Oral Biotechnology, Center for Dental Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany.
Cell Signal. 2019 Nov;63:109382. doi: 10.1016/j.cellsig.2019.109382. Epub 2019 Jul 31.
The HIPPO pathway effector YAP has been shown to be regulated by FAK-signaling. However, the existence of an inverse relationship between YAP and FAK is unknown. Here we demonstrate in hMSCs and in the human osteosarcoma derived cell line Saos that Verteporfin- or RNAi-dependent YAP depletion has opposing influence on FAK. While Verteporfin strikingly reduced cellular FAK protein and phosphorylation, RNAi led to an increase of both molecules and point on a generalizable aspect of the YAP/FAK interrelationship. YAP depletion also caused down-regulation of osteogenic genes in hMSCs, irrespective from the YAP intervention mode. Verteporfin induced topological changes in conjunction with reduced protein levels of β1 integrin, paxillin, and zyxin of focal adhesions (FAs) in hMSCs, suggesting FAK-decrease-related alterations in FAs, which seems to be a FAK-dependent mechanism. On the cell behavioral level, YAP-FAK-interrelation involves proliferation and senescence, as indicated by proliferation inhibition and increase of β-Galactosidase-activity in hMSCs. Our findings, derived from this dual strategy of YAP intervention, reveal a YAP-FAK relationship in conjunction with molecular and cell behavioral consequences. Moreover, they deepen the current scientific knowledge on YAP from a different scientific point of view, since this inverse YAP/FAK-relationship seems to be transferrable to other cell types, including cell entities with pathological background.
HIPPO 通路效应物 YAP 的活性受到 FAK 信号的调控。然而，YAP 和 FAK 之间是否存在相反的关系尚不清楚。在这里，我们在 hMSC 和人骨肉瘤衍生细胞系 Saos 中证明，Verteporfin 或 RNAi 依赖性 YAP 耗竭对 FAK 有相反的影响。虽然 Verteporfin 显著降低了细胞内的 FAK 蛋白和磷酸化水平，但 RNAi 导致这两种分子的增加，并指出了 YAP/FAK 相互关系的一个普遍方面。YAP 耗竭也导致 hMSC 中成骨基因的下调，而与 YAP 干预模式无关。Verteporfin 在 hMSC 中诱导拓扑结构变化，同时减少焦点黏附（FA）β1 整合素、桩蛋白和纽蛋白的蛋白水平，表明 FA 中与 FAK 减少相关的改变，这似乎是一种 FAK 依赖性机制。在细胞行为水平上，YAP-FAK 相互关系涉及增殖和衰老，正如 hMSC 中增殖抑制和β-半乳糖苷酶活性增加所表明的那样。我们的研究结果来自 YAP 干预的这种双重策略，揭示了 YAP-FAK 关系以及分子和细胞行为后果。此外，它们从不同的科学角度深化了当前关于 YAP 的科学知识，因为这种相反的 YAP/FAK 关系似乎可转移到其他细胞类型，包括具有病理背景的细胞实体。
