CBL (Cbl proto-oncogene) encodes an E3 ubiquitin-protein ligase that serves as a critical negative regulator of cellular signaling pathways. The protein functions by accepting ubiquitin from E2 ubiquitin-conjugating enzymes and transferring it to target substrates, promoting their proteasomal degradation 1. CBL comprises an N-terminal phosphotyrosine binding (PTB) domain and a C-terminal region containing a RING finger motif essential for its ubiquitin ligase activity 1. The protein targets activated receptor tyrosine kinases and membrane-bound kinases for ubiquitination and degradation, thereby terminating signaling cascades 1. In immune regulation, CBL-B (the related family member) is upregulated in exhausted CD8+ T cells and activated NK cells, where it negatively regulates effector functions 23. Deficiency of both CBL and CBLB leads to hyper T follicular helper cell responses and systemic lupus erythematosus by preventing BCL6 degradation 4. Clinically, CBL mutations are associated with human myeloid neoplasms, where loss of ubiquitin ligase function acts as a tumor suppressor defect while maintaining oncogenic signaling properties 5. The protein also plays roles in muscle atrophy through IRS-1 degradation 6 and angiogenesis regulation 7.