Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
J Biol Chem. 2024 Mar;300(3):105692. doi: 10.1016/j.jbc.2024.105692. Epub 2024 Jan 30.
PKC is a multifunctional family of Ser-Thr kinases widely implicated in the regulation of fundamental cellular functions, including proliferation, polarity, motility, and differentiation. Notwithstanding their primary cytoplasmic localization and stringent activation by cell surface receptors, PKC isozymes impel prominent nuclear signaling ultimately impacting gene expression. While transcriptional regulation may be wielded by nuclear PKCs, it most often relies on cytoplasmic phosphorylation events that result in nuclear shuttling of PKC downstream effectors, including transcription factors. As expected from the unique coupling of PKC isozymes to signaling effector pathways, glaring disparities in gene activation/repression are observed upon targeting individual PKC family members. Notably, specific PKCs control the expression and activation of transcription factors implicated in cell cycle/mitogenesis, epithelial-to-mesenchymal transition and immune function. Additionally, PKCs isozymes tightly regulate transcription factors involved in stepwise differentiation of pluripotent stem cells toward specific epithelial, mesenchymal, and hematopoietic cell lineages. Aberrant PKC expression and/or activation in pathological conditions, such as in cancer, leads to profound alterations in gene expression, leading to an extensive rewiring of transcriptional networks associated with mitogenesis, invasiveness, stemness, and tumor microenvironment dysregulation. In this review, we outline the current understanding of PKC signaling "in" and "to" the nucleus, with significant focus on established paradigms of PKC-mediated transcriptional control. Dissecting these complexities would allow the identification of relevant molecular targets implicated in a wide spectrum of diseases.
蛋白激酶 C（PKC）是一个多功能丝氨酸-苏氨酸激酶家族，广泛参与调节基本的细胞功能，包括增殖、极性、运动和分化。尽管 PKC 同工酶主要位于细胞质中，并严格通过细胞表面受体激活，但它们推动了显著的核信号转导，最终影响基因表达。虽然转录调节可能由核 PKC 执行，但它通常依赖于导致 PKC 下游效应物（包括转录因子）核穿梭的细胞质磷酸化事件。正如 PKC 同工酶与信号效应途径的独特偶联所预期的那样，针对单个 PKC 家族成员时观察到明显的基因激活/抑制差异。值得注意的是，特定的 PKC 控制细胞周期/有丝分裂、上皮-间充质转化和免疫功能中涉及的转录因子的表达和激活。此外，PKC 同工酶还紧密调节多能干细胞向特定上皮、间充质和造血细胞谱系逐步分化过程中涉及的转录因子。在病理条件下，如癌症中，PKC 表达和/或激活异常会导致基因表达的深刻改变，从而导致与有丝分裂、侵袭性、干性和肿瘤微环境失调相关的转录网络的广泛重布线。在这篇综述中，我们概述了 PKC 信号在核内和核外的当前理解，重点关注已建立的 PKC 介导的转录控制范例。剖析这些复杂性将有助于确定涉及广泛疾病的相关分子靶标。
