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Signal transduction JNK pathway

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Signal transduction JNK pathway

JNK pathway

The Mitogen-activated protein kinases 8-10 ( JNK(MAPK8-10) ) belong to asub-group of evolutionarily conserved mitogen-activated protein kinases (MAPK) activatedprimarily by cytokines, growth factors and by exposure to environmental stress.JNK(MAPK8-10) activity is regulated through multi-tiered cascades composed of MAPKkinases (MAPKK, MKK or MEK) and MAPKK kinase or MEK kinase (MAPKKK or MEKK) [1]. Mitogen-activated protein kinase kinases 4 and 7 ( MEK4(MAP2K4) andMKK7(MAP2K7) ) are the specific MAPK kinase isoforms that activateJNK(MAPK8-10) [2], [3].

Tumor necrosis factor ( TNF-alpha ) signaling is a prominent activator ofJNK(MAPK8-10) pathway. TNF-alpha binds and induces trimerization of Tumornecrosis factor receptor superfamily, member 1A ( TNF-R1 ) and triggers itsassociation with TNFRSF1A-associated via death domain ( TRADD ), that recruits TNFreceptor-associated factor 2 ( TRAF2 ). TRAF2 activates Mitogen-activatedprotein kinase kinase kinase kinases 2, 3, 4 and 5 ( GCK(MAP4K2), GLK(MAP4K3),HGK(MAP4K4) and GCKR(MAP4K5) ). These kinases, in turn, activate downstreamkinases Mitogen-activated protein kinase kinase kinases 1, 7 and 11 (MEKK1(MAP3K1), TAK1(MAP3K7), MLK3(MAP3K11) ). These kinases phosphorylateMEK4(MAP2K4) and MKK7(MAP2K7) that in turn activate JNK(MAPK8-10)[4], [5], [6], [7]. In addition,TRAF2 stimulates Mitogen-activated protein kinase kinase kinase 5 (ASK1(MAP3K5) ) that can directly activate MEK4(MAP2K4) andMKK7(MAP2K7) followed by JNK(MAPK8-10) activation [8], [9].

Growth factors bind to and activate Growth factor receptors. The latter activatev-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-RAS ) via the growth factorreceptor-bound protein 2 ( GRB2 ) / Son of sevenless homologs ( SOS) pathway. H-RAS binds to and a ctivates GCKR(MAP4K5) that in turnphosphorylates and activates MEKK1(MAP3K1). The latter  phosphorylates andactivates JNK(MAPK8-10) [10], [11]. In addition,H-RAS can suppress JNK(MAPK8-10) signaling by recruitment of the v-Raf-1murine leukemia viral oncogene homolog 1 ( c-Raf-1 ). The latter inhibitsASK1(MAP3K5) and its downstream effector JNK(MAPK8-10) [12].

Growth factor signaling also promotes activation of the v-crk sarcoma virus CT10oncogene homolog ( CRK ) that, via recruitment of Mitogen-activated protein kinasekinase kinase kinase 1 ( HPK1(MAP4K1) ), stimulates activity ofMLK3(MAP3K11), MEKK1(MAP3K1) and TAK1(MAP3K7) and their downstreamtargets MEK4(MAP2K4) and MKK7(MAP2K7) thereby leading to activation of theJNK(MAPK8-10) [13], [14].

The Fas ligand ( FasL(TNFSF6) ) can activate JNK(MAPK8-10) pathwaythrough induction of Fas ( FasR(CD95) ) association with Death-domain associatedprotein ( DAXX ) and subsequent activation of ASK1(MAP3K5)/MEK4(MAP2K4) and MKK7(MAP2K7)/ JNK(MAPK8-10) [15],[16], [17], [18].

Small GTPases Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) and Celldivision cycle 42 ( CDC42 ) can activate the JNK(MAPK8-10) pathway bybinding and stimulating the Mitogen-activated protein kinase kinase kinases 4 and 10 (MEKK4(MAP3K4), MLK2(MAP3K10) ) , MLK3(MAP3K11) andMEKK1(MAP3K1) These kinases phosphorylate MEK4(MAP2K4) andMKK7(MAP2K7) followed by JNK(MAPK8-10) activation [19], [20], [21].

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) andMKK7(MAP2K7) [22], [23], [24], [25],[26], [21].

Activated JNK(MAPK8-10) kinases regulate gene expression by phosphorylating awide variety of nuclear targets. First of all, they activate AP-1 family of transcriptionfactors, including Jun oncogene ( c-Jun ), Jun D proto-oncogene ( JunD )and Activating transcription factor 2 ( ATF-2 ) [2], [27]. In addition, they stimulate ELK1 member of ETS oncogene family ( Elk-1) and ELK4 ETS-domain protein ( Elk-4 ) transcriptional activity [28],[29], [27]. JNK(MAPK8-10) kinases also phosphorylate andactivate Tumor protein p53 ( p53 ) and SMAD family member 4 ( SMAD4 )[30], [31], [2], [32]. 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 [33], [27].