Pieles Oliver, Morsczeck Christian
Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
Biomedicines. 2024 Nov 29;12(12):2735. doi: 10.3390/biomedicines12122735.
Protein kinase C (PKC) plays an essential role during many biological processes including development from early embryonic stages until the terminal differentiation of specialized cells. This review summarizes the current knowledge about the involvement of PKC in molecular processes during the differentiation of stem/precursor cells into tissue cells with a particular focus on osteogenic, adipogenic, chondrogenic and neuronal differentiation by using a comprehensive approach. Interestingly, studies examining the overall role of PKC, or one of its three isoform groups (classical, novel and atypical PKCs), often showed controversial results. A discrete observation of distinct isoforms demonstrated that the impact on differentiation differs highly between the isoforms, and that during a certain process, the influence of only some isoforms is crucial, while others are less important. In particular, PKCβ inhibits, and PKCδ strongly supports osteogenesis, whereas it is the other way around for adipogenesis. PKCε is another isoform that overwhelmingly supports adipogenic differentiation. In addition, PKCα plays an important role in chondrogenesis, while neuronal differentiation has been positively associated with numerous isoforms including classical, novel and atypical PKCs. In a cellular context, various upstream mediators, like the canonical and non-canonical Wnt pathways, endogenously control PKC activity and thus, their activity interferes with the influence of PKC on differentiation. Downstream of PKC, several proteins and pathways build the molecular bridge between the enzyme and the control of differentiation, of which only a few have been well characterized so far. In this context, PKC also cooperates with other kinases like Akt or protein kinase A (PKA). Furthermore, PKC is capable of directly phosphorylating transcription factors with pivotal function for a certain developmental process. Ultimately, profound knowledge about the role of distinct PKC isoforms and the involved signaling pathways during differentiation constitutes a promising tool to improve the use of stem cells in regenerative therapies by precisely manipulating the activity of PKC or downstream effectors.
蛋白激酶C（PKC）在许多生物学过程中发挥着至关重要的作用，包括从早期胚胎阶段到特化细胞终末分化的发育过程。本综述通过综合方法总结了目前关于PKC参与干细胞/前体细胞分化为组织细胞过程中分子机制的知识，特别关注成骨、成脂、成软骨和神经元分化。有趣的是，研究PKC及其三个亚型组（经典型、新型和非典型PKC）之一的整体作用时，结果往往存在争议。对不同亚型的单独观察表明，各亚型对分化的影响差异很大，并且在特定过程中，只有某些亚型的影响至关重要，而其他亚型则不太重要。特别是，PKCβ抑制成骨，而PKCδ强烈支持成骨，而成脂过程则相反。PKCε是另一种强烈支持成脂分化的亚型。此外，PKCα在成软骨过程中起重要作用，而神经元分化与包括经典型、新型和非典型PKC在内的多种亚型呈正相关。在细胞环境中，各种上游介质，如经典和非经典Wnt信号通路，内源性地控制PKC活性，因此它们的活性会干扰PKC对分化的影响。在PKC的下游，几种蛋白质和信号通路构成了该酶与分化控制之间的分子桥梁，到目前为止，其中只有少数已得到充分表征。在这种情况下，PKC还与其他激酶如Akt或蛋白激酶A（PKA）协同作用。此外，PKC能够直接磷酸化对特定发育过程具有关键作用的转录因子。最终，深入了解不同PKC亚型在分化过程中的作用以及相关信号通路，有望通过精确调控PKC或其下游效应器的活性，改善干细胞在再生治疗中的应用。
