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). ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein] ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein] Activated by various stressors, including oxidative stress, endoplasmic reticulum stress, and calcium overload, as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) and lipopolysaccharide (LPS). Homophilic association of MAP3K5/ASK1 through the C-terminal coiled-coil domains and the heteromeric complex formation of MAP3K5/ASK1 with the reduced form of thioredoxin (TXN), constitutes an inactive form of the kinase. Upon ROS-induced dissociation of TXN from MAP3K5/ASK1, TRAF2 and TRAF6 are reciprocally recruited to MAP3K5/ASK1 and form the active MAP3K5/ASK1 signalosome, in which TRAF2 and TRAF6 appear to facilitate the active configuration of MAP3K5/ASK1. MAP3K5/ASK1 activity is also regulated through several phosphorylation and dephosphorylation events. Thr-845 is an activating phosphorylation site that is autophosphorylated and phosphorylated by MAP3K6/ASK2 and dephosphorylated by PPP5C. Ser-90 and Ser-1040 are inactivating phosphorylation sites, the former of which is phosphorylated by AKT1. Phosphorylation of Ser-973 induces association of MAP3K5/ASK1 with the 14-3-3 family proteins, which suppresses MAP3K5/ASK1 activity. Calcium/calmodulin-activated protein phosphatase calcineurin (PPP3CA) has been shown to directly dephosphorylate this site. SOCS1 binds to ASK1 by recognizing phosphorylation of Tyr-725 and induces MAP3K5/ASK1 degradation in endothelial cells. Also dephosphorylated and activated by PGAM5. Contains an N-terminal autoinhibitory domain. Homodimer when inactive (By similarity). 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 (By similarity). This complex formation promotes MAP3K5-JNK activation and subsequent apoptosis (By similarity). Interacts with SOCS1 which recognizes phosphorylation of Tyr-725 and induces MAP3K5/ASK1 degradation in endothelial cells (By similarity). Interacts with the 14-3-3 family proteins such as YWHAB, YWHAE, YWHAQ, YWHAH, YWHAZ and SFN (By similarity). Interacts with ARRB2, BIRC2, DAB2IP, IGF1R, MAP3K6/ASK2, PIM1, PGAM5, SOCS1, STUB1, TRAF2 and TXN (By similarity). Interacts with ERN1 in a TRAF2-dependent manner (By similarity). Interacts with calcineurin subunit PPP3R1, PPP5C, PPM1L and TRAF6 (PubMed:15864310, PubMed:16648474, PubMed:17456047, PubMed:22399290). Interacts (via N-terminus) with RAF1 and this interaction inhibits the proapoptotic function of MAP3K5. Interacts with DAB2IP (via N-terminus C2 domain); the interaction occurs in a TNF-alpha-dependent manner (By similarity).Interacts with DUSP13/DUSP13A; may positively regulate apoptosis (By similarity). Interacts with PPIA/CYPA (By similarity). Interacts with PRMT1; the interaction results in MAP3K5 methylation by PRMT1 which inhibits MAP3K5 activation (By similarity). Interacts with TRAF2; the interaction is inhibited by PRMT1 (By similarity). Interacts with TRIM48 (By similarity). Interaction with 14-3-3 proteins alters the distribution of MAP3K5/ASK1 and restricts it to the perinuclear endoplasmic reticulum region. Expressed in various adult mouse tissues including heart, brain, lung, liver and kidney. Ser-90 and Ser-1040 are inactivating phosphorylation sites, the former of which is phosphorylated by AKT1 (By similarity). Phosphorylated at Ser-973 which induces association of MAP3K5/ASK1 with the 14-3-3 family proteins and suppresses MAP3K5/ASK1 activity (PubMed:16648474). Calcineurin (CN) dephosphorylates this site. Also dephosphorylated and activated by PGAM5 (By similarity). Phosphorylated at Thr-845 through autophosphorylation and by MAP3K6/ASK2 which leads to activation (PubMed:11920685, PubMed:18948261, PubMed:22399290). Thr-845 is dephosphorylated by PPP5C (PubMed:22399290). Phosphorylation at Ser-973 in response to oxidative stress is negatively regulated by PPIA/CYPA (By similarity). Ubiquitinated. Tumor necrosis factor (TNF) induces TNFR2-dependent ubiquitination, leading to proteasomal degradation. Ubiquitinated by RC3H2 in a TRIM48-dependent manner. Methylation at Arg-85 and Arg-87 by PRMT1 promotes association of MAP3K5 with thioredoxin and negatively regulates MAP3K5 association with TRAF2, inhibiting MAP3K5 activation. Methylation is blocked by ubiquitination of PRMT1 by TRIM48. Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.