MAP3K5, Mitogen-activated protein kinase kinase kinase 5
Enzyme Classification 18.104.22.168
Also Known as
M3K5_HUMAN, MAP3K5, ASK1, MAPKKK5, MEKK5
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1). Homodimer when inactive. Binds both upstream activators and downstream substrates in multimolecular complexes. Part of a cytoplasmic complex made of HIPK1, DAB2IP and MAP3K5 in response to TNF (PubMed:15310755, PubMed:15701637, PubMed:17210579, PubMed:17389591). This complex formation promotes MAP3K5-JNK activation and subsequent apoptosis. Interacts with SOCS1 which recognizes phosphorylation of Tyr-718 and induces MAP3K5/ASK1 degradation in endothelial cells. Interacts with the 14-3-3 family proteins such as YWHAB, YWHAE, YWHAQ, YWHAH, YWHAZ and SFN (PubMed:10411906, PubMed:15023544, PubMed:15094778). Interacts with ARRB2, BIRC2, DAB2IP, IGF1R, MAP3K6/ASK2, PGAM5, PIM1, PPP5C, SOCS1, STUB1, TRAF2, TRAF6 and TXN (PubMed:9564042,PubMed:9774977, PubMed:10688666, PubMed:11090355, PubMed:11689443, PubMed:12556535, PubMed:12813029, PubMed:15310755, PubMed:16038411, PubMed:16129676, PubMed:16407264, PubMed:17220297, PubMed:17724081, PubMed:18408005, PubMed:19590015, PubMed:19749799). Interacts with ERN1 in a TRAF2-dependent manner (PubMed:14749717). Interacts with calcineurin subunit PPP3R1 and with PPM1L (PubMed:17456047) (By similarity). Interacts (via N-terminus) with RAF1 and this interaction inhibits the proapoptotic function of MAP3K5 (PubMed:11427728). Interacts with DAB2IP (via N-terminus C2 domain); the interaction occurs in a TNF-alpha-dependent manner (PubMed:15310755). Interacts with DUSP13/DUSP13A; may positively regulate apoptosis (PubMed:20358250). Interacts with DAXX (PubMed:9743501). Interacts with RC3H2 (PubMed:24448648).