Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis (     ). Acts as a direct caspase inhibitor ( ). Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry ( , ). Inactivates CASP9 by keeping it in a monomeric, inactive state . Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, RIPK2, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS, PTEN and BIRC5/survivin (   , ). Acts as an important regulator of innate immunity by mediating 'Lys-63'-linked polyubiquitination of RIPK2 downstream of NOD1 and NOD2, thereby transforming RIPK2 into a scaffolding protein for downstream effectors, ultimately leading to activation of the NF-kappa-B and MAP kinases signaling ( , ). 'Lys-63'-linked polyubiquitination of RIPK2 also promotes recruitment of the LUBAC complex to RIPK2 (, ). Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation . Ubiquitination of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation . Ubiquitination of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation (, ). Plays a role in copper homeostasis by ubiquitinating COMMD1 and promoting its proteasomal degradation . Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation . Ubiquitinates and therefore mediates the proteasomal degradation of BCL2 in response to apoptosis . 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 . Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES . Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program .
Subcellular locations: Cytoplasm, Nucleus
TLE3 promotes its nuclear localization.
Expressed in colonic crypts (at protein level) . Ubiquitous, except peripheral blood leukocytes .