NUMB alternative splicing and isoform-specific functions in development and disease

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.