Under nonstress conditions ASK1 is oligomerized (a requirement for its activation) through its C-terminal
coiled-coil domain (CCC), but remains in an inactive form by the suppressive effect of reduced thioredoxin (
Trx) and calcium and integrin binding protein 1 (
CIB1). Trx inhibits ASK1 kinase activity by direct binding to its N-terminal coiled-coil domain (NCC). Trx and CIB1 regulate ASK1 activation in a redox- or calcium- sensitive manner, respectively. Both appear to compete with TNF-α receptor-associated factor 2 (TRAF2), an ASK1 activator.
TRAF2 and
TRAF6 are then recruited to ASK1 to form a larger molecular mass complex. Subsequently, ASK1 forms homo-oligomeric interactions not only through the CCC, but also the NCC, which leads to full activation of ASK1 through autophosphorylation at threonine 845. ASK1 gene transcription can be induced by inflammatory cytokines such as IL-1 and TNF-α through the activation of the
NF-kb protein RelA. Thus, unlike other members of the mitogen-activated protein kinase family, the regulation of ASK1 expression is transcriptional as well as
post-transcriptional. == Interactions ==