PMID- 32330602 OWN - NLM STAT- MEDLINE DCOM- 20210803 LR - 20211204 IS - 1873-3913 (Electronic) IS - 0898-6568 (Linking) VI - 72 DP - 2020 Aug TI - Force-responsive Zyxin modulation in periodontal ligament cells is regulated by YAP rather than TAZ. PG - 109662 LID - S0898-6568(20)30139-X [pii] LID - 10.1016/j.cellsig.2020.109662 [doi] AB - In the context of mechanically induced force transmission, the modification of the actin cytoskeleton through involvement of zyxin is an established concept. However, in cells of the periodontal ligament (PDL), which is physiologically subjected to intermittent mechanical forces, the force-responsive modulation of zyxin and the molecular key players, which orchestrate its cellular regulation, have not yet been elucidated. By employing indirect immunofluorescence and western blotting with different subcellular fractions, we show here in stretch force-exposed human PDL fibroblasts (hPDLFs) that (i) the zyxin protein is modulated, and (ii) its subcellular localization is altered. More importantly, using a pharmacological intervention approach, to inhibit the nuclear presence of the co-transcriptional activator yes-associated protein (YAP), we evidence for the first time that on the molecular level, the cellular abundance of zyxin, among the Thyrotrophic Embryonic Factor (TEF)-binding proteins, is regulated by YAP rather than TAZ. Our findings provide novel insights into the topic how cells of the periodontium and the periodontal ligament in particular respond and may adapt to mechanical forces, and first time identify YAP as the key player of the intracellular regulation of the mechano-sensor and mechano-transducer zyxin in hPDLFs. Moreover, the findings broaden the current knowledge on YAP, since so far, currently only very few YAP-regulated genes have been identified. CI - Copyright (c) 2020 Elsevier Inc. All rights reserved. FAU - Belgardt, Elisa AU - Belgardt E AD - Department of Orthodontics, Center for Dental Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetterstr. 55, 79106 Freiburg, Germany. Electronic address: elisa.sophie.belgardt@uniklinik-freiburg.de. FAU - Steinberg, Thorsten AU - Steinberg T AD - Division of Oral Biotechnology, Center for Dental Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetterstr. 55, 79106 Freiburg, Germany. Electronic address: thorsten.steinberg@uniklinik-freiburg.de. FAU - Husari, Ayman AU - Husari A AD - Department of Orthodontics, Center for Dental Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetterstr. 55, 79106 Freiburg, Germany; Faculty of Engineering, University of Freiburg, Georges-Kohler-Allee 101, 79110 Freiburg, Germany. Electronic address: ayman.husari@uniklinik-freiburg.de. FAU - Dieterle, Martin Philipp AU - Dieterle MP AD - Division of Oral Biotechnology, Center for Dental Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetterstr. 55, 79106 Freiburg, Germany. Electronic address: martin.dieterle@uniklinik-freiburg.de. FAU - Hulter-Hassler, Diana AU - Hulter-Hassler D AD - Department of Orthodontics, Center for Dental Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetterstr. 55, 79106 Freiburg, Germany; Faculty of Biology, University of Freiburg, Schaenzlestr. 1, 79104 Freiburg, Germany. Electronic address: diana.huelter-hassler@uniklinik-freiburg.de. FAU - Jung, Britta AU - Jung B AD - Department of Orthodontics, Center for Dental Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetterstr. 55, 79106 Freiburg, Germany. Electronic address: britta.jung@uniklinik-freiburg.de. FAU - Tomakidi, Pascal AU - Tomakidi P AD - Division of Oral Biotechnology, Center for Dental Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetterstr. 55, 79106 Freiburg, Germany. Electronic address: pascal.tomakidi@uniklinik-freiburg.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200421 PL - England TA - Cell Signal JT - Cellular signalling JID - 8904683 RN - 0 (14-3-3 Proteins) RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (DNA-Binding Proteins) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (TEA Domain Transcription Factors) RN - 0 (TEAD2 protein, human) RN - 0 (Transcription Factors) RN - 0 (Transcriptional Coactivator with PDZ-Binding Motif Proteins) RN - 0 (WWTR1 protein, human) RN - 0 (YAP-Signaling Proteins) RN - 0 (YAP1 protein, human) RN - 0 (Zyxin) RN - 0X9PA28K43 (Verteporfin) SB - IM MH - 14-3-3 Proteins/metabolism MH - Adaptor Proteins, Signal Transducing/*metabolism MH - Adolescent MH - Biomechanical Phenomena MH - DNA-Binding Proteins/metabolism MH - Humans MH - Intracellular Signaling Peptides and Proteins/*metabolism MH - Male MH - Periodontal Ligament/*cytology MH - Stress, Mechanical MH - Subcellular Fractions/metabolism MH - TEA Domain Transcription Factors MH - Transcription Factors/*metabolism MH - Transcriptional Coactivator with PDZ-Binding Motif Proteins MH - Verteporfin/pharmacology MH - YAP-Signaling Proteins MH - Zyxin/*metabolism OTO - NOTNLM OT - Periodontal ligament fibroblasts (PDLFs) OT - Strain OT - TEAD2 OT - YAP/TAZ OT - Zyxin COIS- Declaration of Competing Interest The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. EDAT- 2020/04/25 06:00 MHDA- 2021/08/04 06:00 CRDT- 2020/04/25 06:00 PHST- 2019/10/28 00:00 [received] PHST- 2020/04/16 00:00 [revised] PHST- 2020/04/20 00:00 [accepted] PHST- 2020/04/25 06:00 [pubmed] PHST- 2021/08/04 06:00 [medline] PHST- 2020/04/25 06:00 [entrez] AID - S0898-6568(20)30139-X [pii] AID - 10.1016/j.cellsig.2020.109662 [doi] PST - ppublish SO - Cell Signal. 2020 Aug;72:109662. doi: 10.1016/j.cellsig.2020.109662. Epub 2020 Apr 21.