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c-Jun N-terminal kinases-Wikipedia

c-Jun N-terminal kinases

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Chemical compounds

mitogen-activated protein kinase 8

Mapk8.PNG

Identifiers
Symbol

MAPK8

Alt. symbols JNK1, PRKM8

NCBI gene

5599

HGNC

6881

OMIM

601158

RefSeq

NM_002750

UniProt

P45983

Other data

Locus

Chr. 10

q11.2

mitogen-activated protein kinase 9

Identifiers
Symbol MAPK9
Alt. symbols JNK2, PRKM9

NCBI gene

5601

HGNC

6886

OMIM

602896

RefSeq

NM_002752

UniProt

P45984

Other data

Locus

Chr. 5

q35

mitogen-activated protein kinase 10

Identifiers
Symbol

MAPK10

Alt. symbols JNK3, PRKM10

NCBI gene

5602

HGNC

6872

OMIM

602897

RefSeq

NM_002753

UniProt

P53779

c-Jun N-terminal kinases (JNKs), 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

irradiation, heat shock, and

osmotic

shock. They also play a role in

T cell

differentiation and the cellular

apoptosis

pathway. Activation occurs through a dual phosphorylation of

threonine

(Thr) and

tyrosine

(Tyr) residues within a Thr-

Pro

-Tyr motif located in kinase subdomain VIII. Activation is carried out by two MAP kinase kinases,

MKK4

and

MKK7

, and JNK can be inactivated by Ser/Thr and Tyr

protein phosphatases

.

[1]

It has been suggested that this signaling pathway contributes to inflammatory responses in mammals and insects.[

citation needed

]

Isoforms[

edit

]

The c-Jun N-terminal kinases consist of ten

isoforms

derived from three genes:

JNK1

(four isoforms),

JNK2

(four isoforms) and

JNK3

(two isoforms).

[2]

Each gene is expressed as either 46 kDa or 55 kDa protein kinases, depending upon how the 3′ coding region of the corresponding mRNA is processed. There have been no functional differences documented between the 46 kDa and the 55 kDa isoform, however, a second form of alternative splicing occurs within transcripts of JNK1 and JNK2, yielding JNK1-α, JNK2-α and JNK1-β and JNK2-β. Differences in interactions with protein substrates arise because of the mutually exclusive utilization of two

exons

within the kinase domain.

[1]

c-Jun N-terminal kinase isoforms have the following tissue distribution:

  • JNK1

    and

    JNK2

    are found in all cells and tissues.

    [3]

  • JNK3

    is found mainly in the brain, but is also found in the heart and the testes.

    [3]

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Function[

edit

]

Inflammatory signals, changes in levels of

reactive oxygen species

, ultraviolet radiation, protein synthesis inhibitors, and a variety of stress stimuli can activate JNK. One way this activation may occur is through disruption of the conformation of sensitive

protein phosphatase

enzymes; specific phosphatases normally inhibit the activity of JNK itself and the activity of proteins linked to JNK activation.

[4]

JNKs can associate with

scaffold proteins

JNK interacting proteins

(JIP) as well as their upstream kinases

JNKK1

and

JNKK2

following their activation.

JNK, by phosphorylation, modifies the activity of numerous proteins that reside at the mitochondria or act in the nucleus. Downstream molecules that are activated by JNK include

c-Jun

,

ATF2

,

ELK1

,

SMAD4

,

p53

and

HSF1

. The downstream molecules that are inhibited by JNK activation include

NFAT4

,

NFATC1

and

STAT3

. By activating and inhibiting other small molecules in this way, JNK activity regulates several important cellular functions including cell growth, differentiation, survival and apoptosis.

JNK1 is involved in

apoptosis

,

neurodegeneration

, cell differentiation and proliferation, inflammatory conditions and

cytokine

production mediated by AP-1 (

activation protein 1

) such as

RANTES

,

IL-8

and

GM-CSF

.

[5]

Recently, JNK1 has been found to regulate

Jun

protein turnover

by

phosphorylation

and activation of the

ubiquitin ligase

Itch

.

Neurotrophin

binding to

p75NTR

activates a JNK signaling pathway causing apoptosis of developing neurons. JNK, through a series of intermediates, activates

p53

and p53 activates

Bax

which initiates apoptosis.

TrkA

can prevent p75NTR-mediated JNK pathway apoptosis.

[6]

JNK can directly phosphorylate Bim-EL, a splicing

isoform

of

Bcl-2 interacting mediator of cell death (Bim)

, which activates Bim-EL apoptotic activity. JNK activation is required for apoptosis but

c-jun

, a protein involved in the JNK pathway, is not always required.

[7]

Roles in DNA repair[

edit

]

The packaging of eukaryotic DNA into chromatin presents a barrier to all DNA-based processes that require recruitment of enzymes to their sites of action. To allow repair of double-strand breaks in DNA, the chromatin must be remodeled.

[8]

Chromatin relaxation occurs rapidly at the site of a DNA damage.

[9]

In one of the earliest steps, JNK phosphorylates

SIRT6

on

serine

10 in response to double-strand breaks (DSBs) or other DNA damage, and this step is required for efficient repair of DSBs.

[10]

Phosphorylation of SIRT6 on S10 facilitates the mobilization of SIRT6 to DNA damage sites, where SIRT6 then recruits and mono-phosphorylates poly (ADP-ribose) polymerase 1 (

PARP1

) at DNA break sites.

[10]

Half maximum accumulation of PARP1 occurs within 1.6 seconds after the damage occurs.

[11]

The chromatin remodeler

Alc1

quickly attaches to the product of PARP1 action, a poly-ADP ribose chain,

[9]

allowing half of the maximum chromatin relaxation, presumably due to action of Alc1, by 10 seconds.

[9]

This allows recruitment of the DNA repair enzyme

MRE11

, to initiate DNA repair, within 13 seconds.

[11]

Removal of UV-induced DNA

photoproducts

, during

transcription coupled nucleotide excision repair (TC-NER)

, depends on JNK phosphorylation of

DGCR8

on

serine

153.

[12]

While DGCR8 is usually known to function in microRNA biogenesis, the microRNA-generating activity of DGCR8 is not required for DGCR8-dependent removal of UV-induced photoproducts.

[12]

Nucleotide excision repair

is also needed for repair of oxidative DNA damage due to

hydrogen peroxide

(H2O2), and DGCR8 depleted cells are sensitive to H2O2.

[12]

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In aging[

edit

]

In

Drosophila

, flies with mutations that augment JNK signaling accumulate less oxidative damage and live dramatically longer than wild-type flies.

[13]

[14]

In the tiny roundworm

Caenorhabditis elegans

, loss-of-function mutants of JNK-1 have a decreased life span, while amplified expression of wild-type JNK-1 extends life span by 40%.

[15]

Worms with overexpressed JNK-1 also have significantly increased resistance to oxidative stress and other stresses.

[15]

See also[

edit

]

  • Issoria lathonia.jpg

     

    Biology portal

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References[

edit

]

  1. ^

    a

    b

    Ip YT, Davis RJ (April 1998). “Signal transduction by the c-Jun N-terminal kinase (JNK)–from inflammation to development”. Curr. Opin. Cell Biol. 10 (2): 205–19.

    doi

    :

    10.1016/S0955-0674(98)80143-9

    .

    PMID

     

    9561845

    .

  2. ^

    Waetzig V, Herdegen T (2005). “Context-specific inhibition of JNKs: overcoming the dilemma of protection and damage”. Br. J. Pharmacol. 26 (9): 455–61.

    doi

    :

    10.1016/j.tips.2005.07.006

    .

    PMID

     

    16054242

    .

  3. ^

    a

    b

    Bode AM, Dong Z (August 2007).

    “The Functional Contrariety of JNK”

    . Mol. Carcinog. 46 (8): 591–8.

    doi

    :

    10.1002/mc.20348

    .

    PMC

     

    2832829

    .

    PMID

     

    17538955

    . The protein products of jnk1 and jnk2 are believed to be expressed in every cell and tissue type, whereas the JNK3 protein is found primarily in brain and to a lesser extent in heart and testis

  4. ^

    Vlahopoulos S, Zoumpourlis VC (August 2004). “JNK: a key modulator of intracellular signaling”. Biochemistry Mosc. 69 (8): 844–54.

    doi

    :

    10.1023/B:BIRY.0000040215.02460.45

    .

    PMID

     

    15377263

    .

    S2CID

     

    39149612

    .

  5. ^

    Oltmanns U, Issa R, Sukkar MB, John M, Chung KF (July 2003).

    “Role of c-jun N-terminal kinase in the induced release of GM-CSF, RANTES and IL-8 from human airway smooth muscle cells”

    . Br. J. Pharmacol. 139 (6): 1228–34.

    doi

    :

    10.1038/sj.bjp.0705345

    .

    PMC

     

    1573939

    .

    PMID

     

    12871843

    .

  6. ^

    Aloyz, R. S.; Bamji, S. X.; Pozniak, C. D.; Toma, J. G.; Atwal, J.; Kaplan, D. R.; Miller, F. D. (1998).

    “P53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors”

    . The Journal of Cell Biology. 143 (6): 1691–2303.

    doi

    :

    10.1083/jcb.143.6.1691

    .

    PMC

     

    2132983

    .

    PMID

     

    9852160

    .

  7. ^

    Becker, E. B.; Howell, J.; Kodama, Y.; Barker, P. A.; Bonni, A. (2004).

    “Characterization of the c-Jun N-terminal kinase-BimEL signaling pathway in neuronal apoptosis”

    . The Journal of Neuroscience : The Official Journal of the Society for Neuroscience. 24 (40): 8762–8770.

    doi

    :

    10.1523/JNEUROSCI.2953-04.2004

    .

    PMC

     

    6729963

    .

    PMID

     

    15470142

    .

  8. ^

    Liu B, Yip RK, Zhou Z (2012).

    “Chromatin remodeling, DNA damage repair and aging”

    . Curr. Genomics. 13 (7): 533–47.

    doi

    :

    10.2174/138920212803251373

    .

    PMC

     

    3468886

    .

    PMID

     

    23633913

    .

  9. ^

    a

    b

    c

    Sellou H, Lebeaupin T, Chapuis C, Smith R, Hegele A, Singh HR, Kozlowski M, Bultmann S, Ladurner AG, Timinszky G, Huet S (2016).

    “The poly(ADP-ribose)-dependent chromatin remodeler Alc1 induces local chromatin relaxation upon DNA damage”

    . Mol. Biol. Cell. 27 (24): 3791–3799.

    doi

    :

    10.1091/mbc.E16-05-0269

    .

    PMC

     

    5170603

    .

    PMID

     

    27733626

    .

  10. ^

    a

    b

    Van Meter M, Simon M, Tombline G, May A, Morello TD, Hubbard BP, Bredbenner K, Park R, Sinclair DA, Bohr VA, Gorbunova V, Seluanov A (2016).

    “JNK Phosphorylates SIRT6 to Stimulate DNA Double-Strand Break Repair in Response to Oxidative Stress by Recruiting PARP1 to DNA Breaks”

    . Cell Rep. 16 (10): 2641–50.

    doi

    :

    10.1016/j.celrep.2016.08.006

    .

    PMC

     

    5089070

    .

    PMID

     

    27568560

    .

  11. ^

    a

    b

    Haince JF, McDonald D, Rodrigue A, Déry U, Masson JY, Hendzel MJ, Poirier GG (2008).

    “PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites”

    . J. Biol. Chem. 283 (2): 1197–208.

    doi

    :

    10.1074/jbc.M706734200

    .

    PMID

     

    18025084

    .

  12. ^

    a

    b

    c

    Calses PC, Dhillon KK, Tucker N, Chi Y, Huang JW, Kawasumi M, Nghiem P, Wang Y, Clurman BE, Jacquemont C, Gafken PR, Sugasawa K, Saijo M, Taniguchi T (2017).

    “DGCR8 Mediates Repair of UV-Induced DNA Damage Independently of RNA Processing”

    . Cell Rep. 19 (1): 162–174.

    doi

    :

    10.1016/j.celrep.2017.03.021

    .

    PMC

     

    5423785

    .

    PMID

     

    28380355

    .

  13. ^

    Wang MC, Bohmann D, Jasper H (2003). “JNK signaling confers tolerance to oxidative stress and extends lifespan in Drosophila”. Dev. Cell. 5 (5): 811–6.

    doi

    :

    10.1016/s1534-5807(03)00323-x

    .

    PMID

     

    14602080

    .

  14. ^

    Wang MC, Bohmann D, Jasper H (2005). “JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling”. Cell. 121 (1): 115–25.

    doi

    :

    10.1016/j.cell.2005.02.030

    .

    PMID

     

    15820683

    .

    S2CID

     

    18365708

    .

  15. ^

    a

    b

    Oh SW, Mukhopadhyay A, Svrzikapa N, Jiang F, Davis RJ, Tissenbaum HA (2005).

    “JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16”

    . Proc. Natl. Acad. Sci. U.S.A. 102 (12): 4494–9.

    doi

    :

    10.1073/pnas.0500749102

    .

    PMC

     

    555525

    .

    PMID

     

    15767565

    .

External links[

edit

]

  • JNK+Mitogen-Activated+Protein+Kinases

    at the US National Library of Medicine

    Medical Subject Headings

    (MeSH)

  • Getting a Handle on Cellular JNK

    (from Beaker Blog)

  • MAP Kinase Resource

Retrieved from “

https://en.wikipedia.org/w/index.php?title=C-Jun_N-terminal_kinases&oldid=1024616115

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