UniProt functional annotation for P45984



	UniProt functional annotation for P45984

UniProt code: P45984.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress- activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK9/JNK2. In turn, MAPK9/JNK2 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. In response to oxidative or ribotoxic stresses, inhibits rRNA synthesis by phosphorylating and inactivating the RNA polymerase 1- specific transcription initiation factor RRN3. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including TP53 and YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Upon T-cell receptor (TCR) stimulation, is activated by CARMA1, BCL10, MAP2K7 and MAP3K7/TAK1 to regulate JUN protein levels. Plays an important role in the osmotic stress-induced epithelial tight-junctions disruption. When activated, promotes beta-catenin/CTNNB1 degradation and inhibits the canonical Wnt signaling pathway. Participates also in neurite growth in spiral ganglion neurons. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the regulation of the circadian clock (PubMed:22441692). Phosphorylates POU5F1, which results in the inhibition of POU5F1's transcriptional activity and enhances its proteosomal degradation (By similarity). {ECO:0000250|UniProtKB:Q9WTU6, ECO:0000269|PubMed:22441692}.

Function: MAPK9 isoforms display different binding patterns: alpha-1 and alpha-2 preferentially bind to JUN, whereas beta-1 and beta-2 bind to ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms. JUNB is not a substrate for JNK2 alpha-2, and JUND binds only weakly to it.

Catalytic activity: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.24; Evidence={ECO:0000269|PubMed:11062067, ECO:0000269|PubMed:15805466, ECO:0000269|PubMed:17189706, ECO:0000269|PubMed:17525747, ECO:0000269|PubMed:17875713, ECO:0000269|PubMed:21110917, ECO:0000269|PubMed:21364637, ECO:0000269|PubMed:22441692, ECO:0000269|PubMed:7969172, ECO:0000269|PubMed:8001819, ECO:0000269|PubMed:8654373};

Catalytic activity: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.24; Evidence={ECO:0000269|PubMed:11062067, ECO:0000269|PubMed:15805466, ECO:0000269|PubMed:17189706, ECO:0000269|PubMed:17525747, ECO:0000269|PubMed:17875713, ECO:0000269|PubMed:21110917, ECO:0000269|PubMed:21364637, ECO:0000269|PubMed:22441692, ECO:0000269|PubMed:7969172, ECO:0000269|PubMed:8001819, ECO:0000269|PubMed:8654373};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:11062067};

Activity regulation: Activated by threonine and tyrosine phosphorylation by either of two dual specificity kinases, MAP2K4 and MAP2K7. MAP2K4 shows a strong preference for Tyr-185 while MAP2K7 phosphorylates Tyr-183 preferentially. Inhibited by dual specificity phosphatases, such as DUSP1. {ECO:0000269|PubMed:11062067}.

Subunit: Interacts with MECOM (By similarity). Interacts with DCLK2 (By similarity). Binds to at least four scaffolding proteins, MAPK8IP1/JIP- 1, MAPK8IP2/JIP-2, MAPK8IP3/JIP-3/JSAP1 and SPAG9/MAPK8IP4/JIP-4. These proteins also bind other components of the JNK signaling pathway (By similarity). Interacts with NFATC4 (PubMed:17875713). Interacts with ATF7; the interaction does not phosphorylate ATF7 but acts as a docking site for ATF7-associated partners such as JUN (PubMed:10376527). Interacts with BCL10 (PubMed:17189706). Interacts with CTNNB1 and GSK3B (PubMed:19675674). Interacts with MAPKBP1 (PubMed:28089251). Interacts with POU5F1; phosphorylates POU5F1 at 'Ser-355'. Found in a complex with SH3RF1, RAC2, MAP3K7/TAK1, MAP2K7/MKK7, MAPK8IP1/JIP1 and MAPK8/JNK1 (By similarity). {ECO:0000250|UniProtKB:P49186, ECO:0000250|UniProtKB:Q9WTU6, ECO:0000269|PubMed:10376527, ECO:0000269|PubMed:17189706, ECO:0000269|PubMed:17875713, ECO:0000269|PubMed:19675674, ECO:0000269|PubMed:28089251}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:19675674}. Nucleus {ECO:0000269|PubMed:19675674}. Note=Colocalizes with POU5F1 in the nucleus. {ECO:0000250|UniProtKB:Q9WTU6}.

Domain: The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.

Ptm: Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K7 and MAP2K4, which activates the enzyme. Autophosphorylated in vitro. {ECO:0000269|PubMed:11062067}.

Similarity: Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress- activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK9/JNK2. In turn, MAPK9/JNK2 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. In response to oxidative or ribotoxic stresses, inhibits rRNA synthesis by phosphorylating and inactivating the RNA polymerase 1- specific transcription initiation factor RRN3. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including TP53 and YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Upon T-cell receptor (TCR) stimulation, is activated by CARMA1, BCL10, MAP2K7 and MAP3K7/TAK1 to regulate JUN protein levels. Plays an important role in the osmotic stress-induced epithelial tight-junctions disruption. When activated, promotes beta-catenin/CTNNB1 degradation and inhibits the canonical Wnt signaling pathway. Participates also in neurite growth in spiral ganglion neurons. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the regulation of the circadian clock (PubMed:22441692). Phosphorylates POU5F1, which results in the inhibition of POU5F1's transcriptional activity and enhances its proteosomal degradation (By similarity). {ECO:0000250\|UniProtKB:Q9WTU6, ECO:0000269\|PubMed:22441692}.



Function:		MAPK9 isoforms display different binding patterns: alpha-1 and alpha-2 preferentially bind to JUN, whereas beta-1 and beta-2 bind to ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms. JUNB is not a substrate for JNK2 alpha-2, and JUND binds only weakly to it.


Catalytic activity:		Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.24; Evidence={ECO:0000269\|PubMed:11062067, ECO:0000269\|PubMed:15805466, ECO:0000269\|PubMed:17189706, ECO:0000269\|PubMed:17525747, ECO:0000269\|PubMed:17875713, ECO:0000269\|PubMed:21110917, ECO:0000269\|PubMed:21364637, ECO:0000269\|PubMed:22441692, ECO:0000269\|PubMed:7969172, ECO:0000269\|PubMed:8001819, ECO:0000269\|PubMed:8654373};
Catalytic activity:		Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.24; Evidence={ECO:0000269\|PubMed:11062067, ECO:0000269\|PubMed:15805466, ECO:0000269\|PubMed:17189706, ECO:0000269\|PubMed:17525747, ECO:0000269\|PubMed:17875713, ECO:0000269\|PubMed:21110917, ECO:0000269\|PubMed:21364637, ECO:0000269\|PubMed:22441692, ECO:0000269\|PubMed:7969172, ECO:0000269\|PubMed:8001819, ECO:0000269\|PubMed:8654373};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269\|PubMed:11062067};
Activity regulation:		Activated by threonine and tyrosine phosphorylation by either of two dual specificity kinases, MAP2K4 and MAP2K7. MAP2K4 shows a strong preference for Tyr-185 while MAP2K7 phosphorylates Tyr-183 preferentially. Inhibited by dual specificity phosphatases, such as DUSP1. {ECO:0000269\|PubMed:11062067}.
Subunit:		Interacts with MECOM (By similarity). Interacts with DCLK2 (By similarity). Binds to at least four scaffolding proteins, MAPK8IP1/JIP- 1, MAPK8IP2/JIP-2, MAPK8IP3/JIP-3/JSAP1 and SPAG9/MAPK8IP4/JIP-4. These proteins also bind other components of the JNK signaling pathway (By similarity). Interacts with NFATC4 (PubMed:17875713). Interacts with ATF7; the interaction does not phosphorylate ATF7 but acts as a docking site for ATF7-associated partners such as JUN (PubMed:10376527). Interacts with BCL10 (PubMed:17189706). Interacts with CTNNB1 and GSK3B (PubMed:19675674). Interacts with MAPKBP1 (PubMed:28089251). Interacts with POU5F1; phosphorylates POU5F1 at 'Ser-355'. Found in a complex with SH3RF1, RAC2, MAP3K7/TAK1, MAP2K7/MKK7, MAPK8IP1/JIP1 and MAPK8/JNK1 (By similarity). {ECO:0000250\|UniProtKB:P49186, ECO:0000250\|UniProtKB:Q9WTU6, ECO:0000269\|PubMed:10376527, ECO:0000269\|PubMed:17189706, ECO:0000269\|PubMed:17875713, ECO:0000269\|PubMed:19675674, ECO:0000269\|PubMed:28089251}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:19675674}. Nucleus {ECO:0000269\|PubMed:19675674}. Note=Colocalizes with POU5F1 in the nucleus. {ECO:0000250\|UniProtKB:Q9WTU6}.
Domain:		The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.
Ptm:		Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K7 and MAP2K4, which activates the enzyme. Autophosphorylated in vitro. {ECO:0000269\|PubMed:11062067}.
Similarity:		Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. {ECO:0000305}.