c-Jun N-terminal kinases

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Main article: Mitogen-activated protein kinase
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c-Jun N-terminal kinases (JNKs), were originally identified as

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

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]

Function

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

GM-CSF.[5]

Recently, JNK1 has been found to regulate

Itch
.

c-jun, a protein involved in the JNK pathway, is not always required.[7]

Roles in DNA repair

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.

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

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]

In aging

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

References

  1. ^
    PMID 9561845
    .
  2. PMID 16054242
    .
  3. ^
    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. S2CID 39149612
    .
  5. PMID 12871843
    .
  6. PMID 9852160
    .
  7. PMID 15470142
    .
  8. PMID 23633913
    .
  9. ^
    PMID 27733626
    .
  10. ^
    PMID 27568560
    .
  11. ^
    PMID 18025084
    .
  12. ^
    PMID 28380355
    .
  13. PMID 14602080
    .
  14. S2CID 18365708
    .
  15. ^
    PMID 15767565
    .

External links
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