Dho Sascha E, Othman Kamal, Zhang Yangjing, McGlade C Jane
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
J Biol Chem. 2025 Mar;301(3):108215. doi: 10.1016/j.jbc.2025.108215. Epub 2025 Jan 23.
The NUMB gene encodes a conserved adaptor protein with roles in asymmetric cell division and cell fate determination. First described as an inhibitor of Notch signaling, multifunctional NUMB proteins regulate multiple cellular pathways through protein complexes with ubiquitin ligases, polarity proteins and the endocytic machinery. The vertebrate NUMB protein isoforms were identified over 2 decades ago, yet the majority of functional studies exploring NUMB function in endocytosis, cell migration and adhesion, development and disease have largely neglected the potential for distinct isoform activity in design and interpretation. In this review we consolidate the literature that has directly addressed individual NUMB isoform functions, as well as interpret other functional studies through the lens of the specific isoforms that were utilized. We also summarize the emerging literature on the mechanisms that regulate alternative splicing of NUMB, and how this is subverted in disease. Finally, the importance of relative NUMB isoform expression as a determinant of activity and considerations for future studies of NUMB isoforms as unique proteins with distinct functions are discussed.
NUMB基因编码一种保守的衔接蛋白，在不对称细胞分裂和细胞命运决定中发挥作用。多功能NUMB蛋白最初被描述为Notch信号的抑制剂，它通过与泛素连接酶、极性蛋白和内吞机制形成蛋白复合物来调节多种细胞途径。脊椎动物的NUMB蛋白异构体在20多年前就已被鉴定出来，但在探索NUMB在内吞作用、细胞迁移和黏附、发育及疾病中的功能的大多数功能研究中，在设计和解释时很大程度上忽略了不同异构体活性的可能性。在这篇综述中，我们整合了直接涉及单个NUMB异构体功能的文献，并通过所使用的特定异构体的视角来解释其他功能研究。我们还总结了关于调节NUMB可变剪接机制的新兴文献，以及这一机制在疾病中是如何被颠覆的。最后，讨论了相对NUMB异构体表达作为活性决定因素的重要性，以及将NUMB异构体作为具有不同功能的独特蛋白进行未来研究的考虑因素。
