ASK1
Encyclopedia
Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5) is a member of MAP kinase kinase kinase family and as such a part of mitogen-activated protein kinase
pathway. It activates c-Jun N-terminal kinase (JNK)
and p38 mitogen-activated protein kinases
in a Raf-independent fashion in response to an array of stresses such as oxidative stress
, endoplasmic reticulum stress
and calcium influx. ASK1 has been found to be involved in cancer, diabetes, 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.
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.
with PP5 GADD45B
, Protein kinase R
, CDC25A
, Death associated protein 6
, RB1CC1
, HSPA1A
, C-Raf
, PDCD6
, TRAF2
, PPP5C
, MAPK8IP3
, TRAF6
, MAP2K6
, TRAF5
, MAP3K7
and DUSP19
.
Mitogen-activated protein kinase
Mitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
pathway. It activates c-Jun N-terminal kinase (JNK)
C-Jun N-terminal kinases
c-Jun N-terminal kinases , were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are responsive to stress stimuli, such as cytokines, ultraviolet...
and p38 mitogen-activated protein kinases
P38
P38 or P-38 may refer to:* Lockheed P-38 Lightning, a World War II American fighter aircraft built by Lockheed* p38 mitogen-activated protein kinases, a class of mitogen-activated protein kinases, two British Royal Navy ships...
in a Raf-independent fashion in response to an array of stresses such as oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
, endoplasmic reticulum stress
Unfolded protein response
The unfolded protein response is a cellular stress response related to the endoplasmic reticulum. It is a stress response that has been found to be conserved between all mammalian species, as well as yeast and worm organisms...
and calcium influx. ASK1 has been found to be involved in cancer, diabetes, cardiovascular and neurodegenerative diseases.
MAP3K5 gene coding for the protein is located on chromosome 6 at locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
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-coilCoiled coil
A coiled coil is a structural motif in proteins, in which 2-7 alpha-helices are coiled together like the strands of a rope . Many coiled coil type proteins are involved in important biological functions such as the regulation of gene expression e.g. transcription factors...
domain (CCC), but remains in an inactive form by the suppressive effect of reduced thioredoxin (Trx
Thioredoxin
Thioredoxin is a class of small redox proteins known to be present in all organisms. It plays a role in many important biological processes. In humans, it is encoded by the TXN gene. Loss-of-function mutation of either of the two human thioredoxin genes is lethal at the four-cell stage of the...
) and calcium and integrin binding protein 1 (CIB1
CIB1
Calcium and integrin-binding protein 1 is a protein that in humans is encoded by the CIB1 gene.-Interactions:CIB1 has been shown to interact with RAC3, PSEN2, DNA-PKcs, UBR5 and CD61.-Further reading:...
). 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.
Interactions
ASK1 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with PP5 GADD45B
GADD45B
Growth arrest and DNA-damage-inducible, beta, also known as GADD45B, is a protein which in humans is encoded by the GADD45B gene.- Function :...
, Protein kinase R
Protein kinase R
Protein kinase RNA-activated also known as protein kinase R , interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 is an enzyme that in humans is encoded by the EIF2AK2 gene.PKR protects against viral...
, CDC25A
CDC25A
Cell division cycle 25 homolog A , also known as CDC25A, is a mammalian gene.-Interactions:CDC25A has been shown to interact with ASK1, Epidermal growth factor receptor, C-Raf, CHEK1, Cyclin E1, PIM1 and YWHAB.-Further reading:...
, Death associated protein 6
Death associated protein 6
Death-associated protein 6 also known as DAXX is a protein that in humans is encoded by the DAXX gene.- Function :DAXX, a death-domain-associated protein, was first discovered through its cytoplasmic interaction with the classical death receptor Fas...
, RB1CC1
RB1CC1
RB1-inducible coiled-coil protein 1 is a protein that in humans is encoded by the RB1CC1 gene.-Interactions:RB1CC1 has been shown to interact with PTK2B, ASK1 and PTK2.-Further reading:...
, HSPA1A
HSPA1A
Heat shock 70 kDa protein 1 is a protein that in humans is encoded by the HSPA1A gene.-Interactions:HSPA1A has been shown to interact with ASK1, STUB1, MSR1, BAG3, Parkin , Fanconi anemia, complementation group C, GPR37, HSF1 and AIFM1....
, C-Raf
C-Raf
RAF proto-oncogene serine/threonine-protein kinase also known as proto-oncogene c-RAF or simply c-Raf is an enzyme that in humans is encoded by the RAF1 gene. The c-Raf protein functions in the MAPK/ERK signal transduction pathway as part of a protein kinase cascade...
, PDCD6
PDCD6
Programmed cell death protein 6 is a protein that in humans is encoded by the PDCD6 gene.-Interactions:PDCD6 has been shown to interact with ASK1, PDCD6IP, Fas receptor, ANXA11 and PEF1.-Further reading:...
, TRAF2
TRAF2
TNF receptor-associated factor 2 is a protein that in humans is encoded by the TRAF2 gene.-Interactions:TRAF2 has been shown to interact with BCL10, CD30, CFLAR, IKK2, MAP3K7IP2, CD137, Caveolin 1, CD27, TNFRSF13B, TANK-binding kinase 1, TRAF1, CD40, UBE2N, MAP3K14, MAP4K2, CASP8AP2, HIVEP3,...
, PPP5C
PPP5C
Serine/threonine-protein phosphatase 5 is an enzyme that in humans is encoded by the PPP5C gene.-Interactions:PPP5C has been shown to interact with ASK1, CRY2 GNA12. and Rac1,-Further reading:...
, MAPK8IP3
MAPK8IP3
C-jun-amino-terminal kinase-interacting protein 3 is an enzyme that in humans is encoded by the MAPK8IP3 gene.-Interactions:MAPK8IP3 has been shown to interact with ASK1, C-Raf, PTK2, MAPK10, Mitogen-activated protein kinase 9, MAPK8, MAP2K1, KLC2, MAP2K7, KLC1, MAPK8IP2 and MAP2K4.-Further reading:...
, TRAF6
TRAF6
TRAF6 is a TRAF human protein.-Interactions:TRAF6 has been shown to interact with SDCBP, IRAK2, IRAK1, MAP3K7IP2, MAP3K7IP1, TNFRSF13B, FHL2, CD40, IKBKG, RANK, HSPB2, UBE2N, SIGIRR, TAX1BP1, ASK1, PPP4C, TNFAIP3, Sequestosome 1, MAP3K7 and Ubiquitin C....
, MAP2K6
MAP2K6
Dual specificity mitogen-activated protein kinase kinase 6 also known as MAP kinase kinase 6 or MAPK/ERK kinase 6 is an enzyme that in humans is encoded by the MAP2K6 gene, on chromosome 17.- Function :...
, TRAF5
TRAF5
TNF receptor-associated factor 5 is a protein that in humans is encoded by the TRAF5 gene.-Interactions:TRAF5 has been shown to interact with ASK1, TNFRSF13B, CD134, CD30, CD40, RANK and TNFRSF14.-Further reading:...
, MAP3K7
MAP3K7
Mitogen-activated protein kinase kinase kinase 7 is an enzyme that in humans is encoded by the MAP3K7 gene.-Interactions:MAP3K7 has been shown to interact with Mothers against decapentaplegic homolog 6, MAP3K7IP2, MAP3K7IP1, MAP3K7IP3, ASK1, PPM1B, TRAF6, MAP2K6 and CHUK.-Further reading:...
and DUSP19
DUSP19
Dual specificity protein phosphatase 19 is an enzyme that in humans is encoded by the DUSP19 gene.-Interactions:DUSP19 has been shown to interact with ASK1 and MAP2K7.-Further reading:...
.