NUMB structure and its alternative splicing variants. (A) NUMB PTB and PRR isoform – exons and protein domains. Up panel, the structure of NUMB precursor-mRNA, with exon 6, 10, and 12 depicted as an alternative cassette exon (top). Asterisks indicate exons that undergo alternative splicing during NUMB transcript maturation. Bottom panel, Schematic of full-length NUMB protein, which contains an amino-terminal PTB, a proline-rich region (PRR), two Eps 15 homology regions of aspartic acid–proline–phenylalanine (DPF) motifs and an asparagine–proline–phenylalanine (NPF) motif (bottom). The PTB domain facilitates tyrosine kinase signaling, endocytosis, and membrane localizing. The NPF domain can bind to the endocytic machinery components of Eps15. The PRR domains exist in certain isoforms containing Src homology binding sites involved in intracellular signal transduction. (B) As a result of three alternative splicing events, the NUMB locus can generate six different transcripts. All six isoforms of the human NUMB protein have a similar structure. NUMB isoforms 5/6 are only partial and cover the coding sequence.