St. Anna Children's Cancer Research Institute, 1090 Vienna, Austria.
Department of Pediatrics, Medical University Vienna, 1090 Vienna, Austria.
Cells. 2020 Apr 15;9(4):972. doi: 10.3390/cells9040972.
YAP and TAZ are intracellular messengers communicating multiple interacting extracellular biophysical and biochemical cues to the transcription apparatus in the nucleus and back to the cell/tissue microenvironment interface through the regulation of cytoskeletal and extracellular matrix components. Their activity is negatively and positively controlled by multiple phosphorylation events. Phenotypically, they serve an important role in cellular plasticity and lineage determination during development. As they regulate self-renewal, proliferation, migration, invasion and differentiation of stem cells, perturbed expression of YAP/TAZ signaling components play important roles in tumorigenesis and metastasis. Despite their high structural similarity, YAP and TAZ are functionally not identical and may play distinct cell type and differentiation stage-specific roles mediated by a diversity of downstream effectors and upstream regulatory molecules. However, YAP and TAZ are frequently looked at as functionally redundant and are not sufficiently discriminated in the scientific literature. As the extracellular matrix composition and mechanosignaling are of particular relevance in bone formation during embryogenesis, post-natal bone elongation and bone regeneration, YAP/TAZ are believed to have critical functions in these processes. Depending on the differentiation stage of mesenchymal stem cells during endochondral bone development, YAP and TAZ serve distinct roles, which are also reflected in bone tumors arising from the mesenchymal lineage at different developmental stages. Efforts to clinically translate the wealth of available knowledge of the pathway for cancer diagnostic and therapeutic purposes focus mainly on YAP and TAZ expression and their role as transcriptional co-activators of TEAD transcription factors but rarely consider the expression and activity of pathway modulatory components and other transcriptional partners of YAP and TAZ. As there is a growing body of evidence for YAP and TAZ as potential therapeutic targets in several cancers, we here interrogate the applicability of this concept to bone tumors. To this end, this review aims to summarize our current knowledge of YAP and TAZ in cell plasticity, normal bone development and bone cancer.
YAP 和 TAZ 是细胞内信使，将多种相互作用的细胞外生物物理和生化线索传递到核内的转录装置，并通过细胞骨架和细胞外基质成分的调节反馈回到细胞/组织微环境界面。它们的活性受到多种磷酸化事件的负向和正向调控。表型上，它们在发育过程中的细胞可塑性和谱系决定中起着重要作用。由于它们调节干细胞的自我更新、增殖、迁移、侵袭和分化，YAP/TAZ 信号传导成分的失调在肿瘤发生和转移中起着重要作用。尽管它们具有高度的结构相似性，但 YAP 和 TAZ 在功能上并不相同，并且可能通过多种下游效应子和上游调节分子发挥不同的细胞类型和分化阶段特异性作用。然而，YAP 和 TAZ 经常被视为功能冗余，并且在科学文献中没有得到充分区分。由于细胞外基质组成和力学信号在胚胎发生过程中的骨形成、出生后骨伸长和骨再生中具有特别重要的意义，因此 YAP/TAZ 被认为在这些过程中具有关键功能。根据软骨内骨发育过程中间充质干细胞的分化阶段，YAP 和 TAZ 发挥不同的作用，这也反映在不同发育阶段间充质谱系起源的骨肿瘤中。为了将大量关于癌症诊断和治疗途径的知识转化为临床应用，主要集中在 YAP 和 TAZ 的表达及其作为 TEAD 转录因子转录共激活因子的作用，但很少考虑途径调节成分的表达和活性以及 YAP 和 TAZ 的其他转录伙伴。由于越来越多的证据表明 YAP 和 TAZ 是几种癌症的潜在治疗靶点，我们在这里探讨了这一概念在骨肿瘤中的适用性。为此，本综述旨在总结我们目前对 YAP 和 TAZ 在细胞可塑性、正常骨发育和骨癌中的认识。
