Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, mitogenic kinase signaling, and cell proliferation, as well as cell invasion and metastasis. Acts as an E3 ubiquitin- protein ligase regulating NF-kappa-B signaling and regulates both canonical and non-canonical NF-kappa-B signaling by acting in opposite directions: acts as a positive regulator of the canonical pathway and suppresses constitutive activation of non-canonical NF-kappa-B signaling. The target proteins for its E3 ubiquitin- protein ligase activity include: RIPK1, RIPK2, RIPK3, RIPK4, CASP3, CASP7, CASP8, TRAF2, DIABLO/SMAC, MAP3K14/NIK, MAP3K5/ASK1, IKBKG/NEMO and MXD1/MAD1. Can also function as an E3 ubiquitin- protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Acts as an important regulator of innate immune signaling via regulation of Toll-like receptors (TLRs), Nodlike receptors (NLRs) and RIG-I like receptors (RLRs), collectively referred to as pattern recognition receptors (PRRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Can stimulate the transcriptional activity of E2F1. Plays a role in the modulation of the cell cycle. Interacts with DIABLO/SMAC and with PRSS25; these interactions inhibit apoptotic suppressor activity. Interacts with CASP9. Interacts (via BIR domains) with TRAF2. Interacts with E2F1, RIPK1, RIPK2, RIPK3, RIPK4, BIRC5/survivin and USP19. Present in many fetal and adult tissues. Mainly expressed in adult skeletal muscle, thymus, testis, ovary, and pancreas, low or absent in brain and peripheral blood leukocytes. The CARD domain inhibits the activation of E3 ubiquitin ligase activity by preventing RING domain dimerization and E2 ubiquitin donor binding and activation. The CARD domain- mediated autoinhibition of the E3 ubiquitin-protein ligase activity suppresses cell proliferation and migration. USP19 regulates the stability of BIRC2/c-IAP1 by preventing its ubiquitination. Belongs to the IAP family. Note: This description may include information from UniProtKB.
Protein type: Ligase; Ubiquitin ligase; EC 6.3.2.-; Ubiquitin conjugating system
Cellular Component: internal side of plasma membrane; nucleus; cytosol
Molecular Function: protein binding; zinc ion binding; transcription coactivator activity; ubiquitin-protein ligase activity; protein N-terminus binding
Biological Process: proteasomal ubiquitin-dependent protein catabolic process; regulation of toll-like receptor signaling pathway; positive regulation of I-kappaB kinase/NF-kappaB cascade; protein polyubiquitination; transcription, DNA-dependent; apoptosis; regulation of cell cycle; regulation of cell proliferation; regulation of innate immune response; cell surface receptor linked signal transduction; regulation of transcription, DNA-dependent; regulation of cell differentiation; regulation of inflammatory response; cell structure disassembly during apoptosis; negative regulation of apoptosis; placenta development
SS: The number of records in which this modification site was determined using site-specific methods. SS methods include amino acid sequencing, site-directed mutagenesis, modification site-specific antibodies, specific MS strategies, etc.