ASK1, Active

Mitogen-activated protein kinase (MAPK) signaling cascades include MAPK or ERK, MAPK kinase (MKK or MEK), and MAPK kinase kinase (MAPKKK or MEKK). MAPKK kinase/MEKK phosphorylates and activates its downstream protein kinase, MAPK kinase/MEK, which in turn activates MAPK. ASK1 (MAPKKK5) contains 1,374 amino acids with all 11 kinase subdomains. Northern blot analysis shows that MAPKKK5 transcript is abundantly expressed in human heart and pancreas. The MAPKKK5 protein phosphorylates and activates MKK4 (aliases SERK1, MAPKK4) in vitro, and activates c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) during transient expression in COS and 293 cells; MAPKKK5 does not activate MAPK/ERK (1). ASK1 also activates MKK3, MKK4 (SEK1), and MKK6. Overexpression of ASK1 induces apoptotic cell death, and ASK1 is activated in cells treated with tumor necrosis factor-α (2). ASK1 interacts with members of the TRAF family and is activated by TRAF2 in the TNF-signaling pathway. After activation by TRAF2, ASK1 activates MKK4, which in turn activates JNK. Thus, ASK1 is a mediator of TRAF2-induced JNK activation (3). Fas triggers cell death specifically in motor neurons by transcriptional upregulation of neuronal nitric oxide synthase (nNOS) mediated by p38 kinase. ASK1 and Daxx act upstream of p38 in the Fas signaling pathway, which was unique to motor neurons and may contribute to motor neuron loss in ALS. (4)