Rac1, CRK, FasR(CD95), LZK(MAP3K13), ATF-2, GRB2, MEKK1(MAP3K1), MAP3K3, Elk-1, MLK3(MAP3K11), GLK(MAP4K3), MEKK4(MAP3K4), TRADD, HPK1(MAP4K1), JNK(MAPK8-10), GCKR(MAP4K5), DAXX, ASK1 (MAP3K5), JunD, MEK4(MAP2K4), TNF-alpha, NF-AT4(NFATC3), FasL(TNFSF6), H-Ras, TAK1(MAP3K7), MKK7 (MAP2K7), MLK2(MAP3K10), GCK(MAP4K2), CDC42, p53, SMAD4, ZPK(MAP3K12), TPL2(MAP3K8), TRAF2, NF-AT2(NFATC1), Elk-4, SOS, MAP3K2 (MEKK2), c-Jun, TNF-R1, JNK1(MAPK8), c-Raf-1, HGK(MAP4K4)
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 ( GCK(MAP4K2), GLK(MAP4K3), 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 a ctivates 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 JNK(MAPK8-10) .
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 MLK3(MAP3K11), MEKK1(MAP3K1) 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 MKK7(MAP2K7)/ JNK(MAPK8-10) , , , .
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), MLK2(MAP3K10) ) , 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), MAP3K3, TPL2(MAP3K8), 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 ) and SMAD family member 4 ( SMAD4 ) , , , . Besides, JNK(MAPK8-10) can negatively regulate Nuclear factors of activated T-cells, cytoplasmic, calcineurin-dependent 1 and 3 ( NF-AT2(NFATC1), NF-AT4(NFATC3) ) activity , .