Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5) is a member of MAP kinase family and as such a part of
mitogen-activated protein kinase
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflamma ...
pathway. It activates
c-Jun N-terminal kinase (JNK) and
p38 mitogen-activated protein kinases
p38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell diffe ...
in a Raf-independent fashion in response to an array of stresses such as
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
,
endoplasmic reticulum stress and calcium influx. ASK1 has been found to be involved in cancer, diabetes,
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...
, cardiovascular and neurodegenerative diseases.
''MAP3K5'' gene coding for the protein is located on chromosome 6 at
locus 6q22.33.
and the transcribed protein contains 1,374 amino acids with 11 kinase subdomains. Northern blot analysis shows that MAP3K5 transcript is abundant in human heart and pancreas.
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).
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
TNF receptor-associated factor 2 is a protein that in humans is encoded by the ''TRAF2'' gene.
Function
The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins associate with, a ...
and
TRAF6
TRAF6 is a TRAF human protein.
Function
The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from members of the TNF rece ...
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.
Interestingly,
TNF-α is also able to stabilize the ASK1 protein through
deubiquitination.
Thus, unlike other members of the mitogen-activated protein kinase family, the regulation of ASK1 expression is transcriptional as well as
post-transcriptional.
Interactions
ASK1 has been shown to
interact with:
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C-Raf
RAF proto-oncogene serine/threonine-protein kinase, also known as proto-oncogene c-RAF or simply c-Raf or even Raf-1, is an enzyme that in humans is genetic code, encoded by the ''RAF1'' gene. The c-Raf protein is part of the MAPK/ERK pathway, E ...
,
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CDC25A,
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DAXX,
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DUSP19,
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EIF2AK2,
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GADD45B,
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HSPA1A,
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MAP2K6,
[ and
* MAPK8IP3,]TRAF2
TNF receptor-associated factor 2 is a protein that in humans is encoded by the ''TRAF2'' gene.
Function
The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins associate with, a ...
,[ and
* ]TRAF6
TRAF6 is a TRAF human protein.
Function
The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from members of the TNF rece ...
.
References
External links
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Further reading
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Programmed cell death
EC 2.7.11
Apoptosis