CBLL2 (Cbl proto-oncogene like 2) is an E3 ubiquitin ligase that catalyzes covalent attachment of ubiquitin moieties to substrate proteins 1. The protein contains a RING finger domain conferring E3 ubiquitin ligase activity and may operate on tyrosine-phosphorylated SRC substrates 1. CBLL2 shows testis-specific expression, with protein localization in spermatocytes, spermatids, Leydig cells, and mature sperm, particularly in the postacrosomal perinuclear theca and sperm tail 1. Its expression is regulated by promoter demethylation, with CpG island methylation silencing the gene in normal lung tissues while demethylation activates it in testicular and lung cancer tissues, identifying it as a cancer/testis antigen 2. The gene's promoter activity is directly inhibited by methylation of its CpG island region 2. Given its E3 ubiquitin ligase function and restricted expression pattern, CBLL2 likely plays a role in spermatogenesis and quality control mechanisms during sperm production. Its aberrant expression in lung cancers through promoter demethylation suggests potential involvement in cancer biology, though direct clinical significance remains to be fully established.