Protocadherins (Pcdhs) are cell adhesion molecules that belong to the cadherin superfamily, and are subdivided into clustered (cPcdhs) and non-clustered Pcdhs (ncPcdhs) in vertebrates. In this review, we summarize their discovery, expression mechanisms, and roles in neuronal development and cancer, thereby highlighting the context-dependent nature of their actions. We furthermore provide an extensive overview of current structural knowledge, and its implications concerning extracellular interactions between cPcdhs, ncPcdhs, and classical cadherins. Next, we survey the known molecular action mechanisms of Pcdhs, emphasizing the regulatory functions of proteolytic processing and domain shedding. In addition, we outline the importance of Pcdh intracellular domains in the regulation of downstream signaling cascades, and we describe putative Pcdh interactions with intracellular molecules including components of the WAVE complex, the Wnt pathway, and apoptotic cascades. Our overview combines molecular interaction data from different contexts, such as neural development and cancer. This comprehensive approach reveals potential common Pcdh signaling hubs, and points out future directions for research. Functional studies of such key factors within the context of neural development might yield innovative insights into the molecular etiology of Pcdh-related neurodevelopmental disorders.

原钙粘蛋白 (Pcdhs) 是属于钙粘蛋白超家族的细胞粘附分子，在脊椎动物中分为簇状 (cPcdhs) 和非簇状 Pcdhs (ncPcdhs)。在这篇综述中，我们总结了它们的发现、表达机制以及在神经元发育和癌症中的作用，从而强调了它们的行为的背景依赖性性质。我们还提供了对当前结构知识的广泛概述，及其对 cPcdhs、ncPcdhs 和经典钙粘蛋白之间细胞外相互作用的影响。接下来，我们调查了 Pcdh 的已知分子作用机制，强调蛋白水解加工和结构域脱落的调节功能。此外，我们概述了 Pcdh 胞内结构域在下游信号级联调节中的重要性，并描述了假定的 Pcdh 与胞内分子的相互作用，包括 WAVE 复合物、Wnt 通路和凋亡级联的成分。我们的概述结合了来自不同背景的分子相互作用数据，例如神经发育和癌症。这种综合方法揭示了潜在的常见 Pcdh 信号中枢，并指出了未来的研究方向。在神经发育背景下对这些关键因素进行功能研究可能会对 Pcdh 相关神经发育障碍的分子病因学产生创新的见解。