The Mitogen-activated protein kinases 8-10
(JNK(MAPK8-10)) belong to a sub-group of evolutionarily
conserved mitogen-activated protein kinases (MAPK) activated primarily by cytokines,
growth factors and by exposure to environmental stress. JNK(MAPK8-10)
activity is regulated through multi-tiered cascades composed of MAPK
kinases (MAPKK, MKK or MEK) and MAPKK kinase or MEK kinase (MAPKKK or MEKK) . Mitogen-activated protein kinase kinases 4 and 7
(MEK4(MAP2K4) and MKK7(MAP2K7))
are the specific MAPK kinase isoforms that activate JNK(MAPK8-10)
Tumor necrosis factor (TNF-alpha) signaling is a
prominent activator of JNK(MAPK8-10) pathway.
TNF-alpha binds and induces trimerization of Tumor necrosis
factor receptor superfamily, member 1A (TNF-R1) and triggers
its association with TNFRSF1A-associated via death domain
(TRADD), that recruits TNF receptor-associated factor 2
(TRAF2). TRAF2 activates
Mitogen-activated protein kinase kinase kinase kinases 2, 3, 4 and 5
HGK(MAP4K4) and GCKR(MAP4K5)).
These kinases, in turn, activate downstream kinases Mitogen-activated protein kinase
kinase kinases 1, 7 and 11 (MEKK1(MAP3K1),
TAK1(MAP3K7), MLK3(MAP3K11)). These kinases phosphorylate
MEK4(MAP2K4) and MKK7(MAP2K7)
that in turn activate JNK(MAPK8-10) , , , . In addition, TRAF2
stimulates Mitogen-activated protein kinase kinase kinase 5
(ASK1(MAP3K5)) that can directly activate
MEK4(MAP2K4) and MKK7(MAP2K7)
followed by JNK(MAPK8-10) activation , .
Growth factors bind to and activate Growth factor receptors. The latter activate
v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-RAS)
via the growth factor receptor-bound protein 2
(GRB2)/ Son of sevenless
homologs (SOS) pathway. H-RAS
binds to and activates
GCKR(MAP4K5) that in turn phosphorylates and activates
MEKK1(MAP3K1). The latter phosphorylates and activates
JNK(MAPK8-10) , . In addition,
H-RAS can suppress
JNK(MAPK8-10) signaling by recruitment of the v-Raf-1 murine
leukemia viral oncogene homolog 1 (c-Raf-1). The latter
inhibits ASK1(MAP3K5) and its downstream effector
Growth factor signaling also promotes activation of the v-crk sarcoma virus CT10
oncogene homolog (CRK) that, via recruitment of
Mitogen-activated protein kinase kinase kinase kinase 1
(HPK1(MAP4K1)), stimulates activity of
and TAK1(MAP3K7) and their downstream targets
MEK4(MAP2K4) and MKK7(MAP2K7)
thereby leading to activation of the
JNK(MAPK8-10) , .
The Fas ligand (FasL(TNFSF6)) can activate
JNK(MAPK8-10) pathway through induction of Fas
(FasR(CD95)) association with Death-domain associated
protein (DAXX) and subsequent activation of
ASK1(MAP3K5)/ MEK4(MAP2K4) and
, , , .
Small GTPases Ras-related C3 botulinum toxin substrate 1
(Rac1) and Cell division cycle 42
(CDC42) can activate the
JNK(MAPK8-10) pathway by binding and stimulating the
Mitogen-activated protein kinase kinase kinases 4 and 10 (MEKK4(MAP3K4),
MLK3(MAP3K11) and MEKK1(MAP3K1)
These kinases phosphorylate MEK4(MAP2K4) and
MKK7(MAP2K7) followed by JNK(MAPK8-10)
activation , , .
Some protein kinases, including Mitogen-activated protein kinase kinase kinases 2, 3,
8, 12 and 13 (MAP3K2(MEKK2),
ZPK(MAP3K12) and LZK(MAP3K13))
can also promote JNK(MAPK8-10) signaling via phosphorylation
and activation of MEK4(MAP2K4) and
MKK7(MAP2K7) , , , , , .
Activated JNK(MAPK8-10) kinases regulate gene expression
by phosphorylating a wide variety of nuclear targets. First of all, they activate AP-1
family of transcription factors, including Jun oncogene
(c-Jun), Jun D proto-oncogene
(JunD) and Activating transcription factor 2
(ATF-2) , . In addition,
they stimulate ELK1 member of ETS oncogene family (Elk-1)
and ELK4 ETS-domain protein (Elk-4) transcriptional activity
, , .
JNK(MAPK8-10) kinases also phosphorylate and activate Tumor
protein p53 (p53). Besides,
JNK(MAPK8-10) can negatively regulate Nuclear factors of
activated T-cells, cytoplasmic, calcineurin-dependent 1 and 3
NF-AT4(NFATC3)) activity , .
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