MAP3K5 gene coding for the protein is located on chromosome 6 at
locus 6q22.33.[7] and the transcribed protein contains 1,374 amino acids with 11 kinase subdomains.[citation needed] Northern blot analysis shows that MAP3K5 transcript is abundant in human heart and pancreas.[8]
Mechanism of activation
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).[9] 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.[10] 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.[11]
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.[6] Interestingly,
TNF-α is also able to stabilize the ASK1 protein through
deubiquitination.[12] Thus, unlike other members of the mitogen-activated protein kinase family, the regulation of ASK1 expression is transcriptional as well as
post-transcriptional.[6]
^Hwang IS, Jung YS, Kim E (October 2002). "Interaction of ALG-2 with ASK1 influences ASK1 localization and subsequent JNK activation". FEBS Letters. 529 (2–3): 183–7.
doi:
10.1016/S0014-5793(02)03329-X.
PMID12372597.
S2CID9264865.
Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, et al. (January 1997). "Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways". Science. 275 (5296): 90–4.
doi:
10.1126/science.275.5296.90.
PMID8974401.
S2CID23981616.
Wang XS, Diener K, Tan TH, Yao Z (December 1998). "MAPKKK6, a novel mitogen-activated protein kinase kinase kinase, that associates with MAPKKK5". Biochemical and Biophysical Research Communications. 253 (1): 33–7.
doi:
10.1006/bbrc.1998.9749.
PMID9875215.
MAP3K5 gene coding for the protein is located on chromosome 6 at
locus 6q22.33.[7] and the transcribed protein contains 1,374 amino acids with 11 kinase subdomains.[citation needed] Northern blot analysis shows that MAP3K5 transcript is abundant in human heart and pancreas.[8]
Mechanism of activation
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).[9] 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.[10] 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.[11]
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.[6] Interestingly,
TNF-α is also able to stabilize the ASK1 protein through
deubiquitination.[12] Thus, unlike other members of the mitogen-activated protein kinase family, the regulation of ASK1 expression is transcriptional as well as
post-transcriptional.[6]
^Hwang IS, Jung YS, Kim E (October 2002). "Interaction of ALG-2 with ASK1 influences ASK1 localization and subsequent JNK activation". FEBS Letters. 529 (2–3): 183–7.
doi:
10.1016/S0014-5793(02)03329-X.
PMID12372597.
S2CID9264865.
Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, et al. (January 1997). "Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways". Science. 275 (5296): 90–4.
doi:
10.1126/science.275.5296.90.
PMID8974401.
S2CID23981616.
Wang XS, Diener K, Tan TH, Yao Z (December 1998). "MAPKKK6, a novel mitogen-activated protein kinase kinase kinase, that associates with MAPKKK5". Biochemical and Biophysical Research Communications. 253 (1): 33–7.
doi:
10.1006/bbrc.1998.9749.
PMID9875215.