Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein 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 protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...

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 differe ...

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 Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...

endoplasmic reticulum stress Beta cells are heavily engaged in the synthesis and secretion of insulin. They are therefore particularly sensitive to endoplasmic reticulum (ER) stress and the subsequent unfolded protein response (UPR). Severe or prolonged episodes of ER st ...

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 joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...

, cardiovascular and neurodegenerative diseases. ''MAP3K5'' gene coding for the protein is located on chromosome 6 at

locus Locus (plural loci) is Latin for "place". It may refer to: Entertainment * Locus (comics), a Marvel Comics mutant villainess, a member of the Mutant Liberation Front * ''Locus'' (magazine), science fiction and fantasy magazine ** ''Locus Award' ...

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 A coiled coil is a structural motif in proteins in which 2–7 alpha helix, alpha-helices are coiled together like the strands of a rope. (Protein dimer, Dimers and Protein trimer, trimers are the most common types.) Many coiled coil-type protei ...

domain (CCC), but remains in an inactive form by the suppressive effect of reduced thioredoxin ( Trx) and calcium and integrin binding protein 1 (

CIB1 Calcium and integrin-binding protein 1 is a protein that in humans is encoded by the ''CIB1'' gene. The protein encoded by this gene is a member of the calcium-binding protein family. The specific function of this protein has not yet been determ ...

). 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, an ...

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 recep ...

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 Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

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 Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with: *

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 encoded by the ''RAF1'' gene. The c-Raf protein is part of the ERK1/2 pathway as a MAP kinase ( ...

, *

CDC25A M-phase inducer phosphatase 1 also known as dual specificity phosphatase Cdc25A is a protein that in humans is encoded by the cell division cycle 25 homolog A (CDC25A) gene. Function CDC25A is a member of the CDC25 family of dual-specificity ...

, *

DAXX 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 r ...

, *

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 Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated pro ...

, * EIF2AK2, *

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 This gene is a member of a group of genes whose transcript levels are increased following stressful ...

, *

HSPA1A Heat shock 70 kDa protein 1, also termed Hsp72, is a protein that in humans is encoded by the ''HSPA1A'' gene. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfo ...

, *

MAP2K6 Dual specificity mitogen-activated protein kinase kinase 6 also known as MAP kinase kinase 6 (MAPKK 6) or MAPK/ERK kinase 6 is an enzyme that in humans is encoded by the ''MAP2K6'' gene, on chromosome 17. Function MAPKK 6 is a member of the d ...

, *

MAP3K7 Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1, is an enzyme that in humans is encoded by the ''MAP3K7'' gene. Structure TAK1 is an evolutionarily conserved kinase in the MAP3 K family and clusters with the tyro ...

and *

MAPK8IP3 C-jun-amino-terminal kinase-interacting protein 3 is an enzyme that in humans is encoded by the ''MAPK8IP3'' gene. The protein encoded by this gene shares similarity with the product of Drosophila syd gene, required for the functional interaction ...

, *

PDCD6 Programmed cell death protein 6 is a protein that in humans is encoded by the ''PDCD6'' gene. This gene encodes a calcium-binding protein belonging to the penta-EF-hand protein family. Calcium binding is important for homodimerization and for con ...

, *

PPP5C Serine/threonine-protein phosphatase 5 is an enzyme that in humans is encoded by the ''PPP5C'' gene. Model organisms Model organisms have been used in the study of PPP5C function. A conditional knockout mouse line, called ''Ppp5ctm1a(EUCOMM) ...

, *

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 PTK2 protein tyrosine kinase 2 (PTK2), also known as focal adhesion ...

, *

TRAF5 TNF receptor-associated factor 5 is a protein that in humans is encoded by the ''TRAF5'' gene. Function The scaffold protein encoded by this gene is a member of the tumor necrosis factor receptor-associated factor (TRAF) protein family and con ...

, and *

Research

A paper published on 28 June 2022 demonstrated that MAP3K5 may be one of the potential targets of ALS. It is found that MAP3K5 is upregulated in both CNS fALS and sALS using an AI-enabled biological target discovery platform. With target discovery, several pathways and drugs and be further designed to treat ALS.

References

External links

* *

Mechanism of activation

Interactions

Research

References

External links

Further reading