NUMBL (NUMB like endocytic adaptor protein) is an endocytic adaptor required for mammalian neurogenesis. It maintains neural progenitor cells during embryonic development and postnatally regulates subventricular zone neuroblast survival and ependymal wall integrity. NUMBL negatively regulates NF-κB signaling by preventing MAP3K7IP2 interaction with polyubiquitinated TRAF6 and RIPK1, and by promoting TRAF6 degradation in cortical neurons. It also functions in mammary gland development, where it specifies myoepithelial cell fate and supports lactogenesis through Notch pathway repression 1. In disease contexts, NUMBL dysfunction has distinct roles across pathologies. Rare deleterious variants in NUMBL were enriched in pediatric patients with multisystem inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection, causing dominant-negative effects that elevated Notch1 signaling and destabilized regulatory T cells 2. In cancer, NUMBL and its homolog NUMB exhibit mutual exclusivity in human tumors and act as tumor suppressors by inhibiting aberrant Notch pathway activation 3. Genetic alterations and gene amplification of NUMBL occur in gliomas and other nervous system tumors 4, and abnormal NUMBL expression correlates with clinicopathologic stage and survival across multiple cancer types 5. These findings indicate NUMBL as a multifunctional regulator whose loss contributes to both inflammatory and neoplastic disease.