DESI2 (desumoylating isopeptidase 2) functions as a dual-specificity enzyme with both deubiquitinating and desumoylating activities. The protein exhibits deubiquitinating activity toward K48- and K63-linked polyubiquitin chains, notably stabilizing ribosomal protein RPS7 through K48-linked deubiquitination 1. DESI2 also demonstrates palmitoyl protein thioesterase activity [UniProt]. Mechanistically, DESI2 acts as a tumor suppressor by regulating the PI3K/AKT/mTOR signaling pathway - overexpression inhibits cell proliferation and promotes apoptosis, while silencing has opposite effects 2. In pancreatic cancer, DESI2 expression is significantly decreased, correlating with increased phosphorylation of AKT/mTOR pathway components 3. Additionally, DESI2 functions in hematopoietic malignancies by binding to and stabilizing JAK2-V617F through desumoylation and deubiquitination at lysine 962 4. Disease relevance includes roles in multiple cancers - reduced expression in pancreatic ductal adenocarcinoma correlates with poor differentiation 3, and it serves as a target of miR-132 in pancreatic islets affecting insulin secretion 5. Clinically, DESI2 represents a potential therapeutic target, with combination gene therapy showing enhanced antitumor efficacy 1, and selective DESI2 inhibitors demonstrating promise against JAK2-mutant leukemias 4.