Q5RFL3 (M3K7_PONAB) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Mitogen-activated protein kinase kinase kinase 7
EC=2.7.11.25

Gene names

Name:

MAP3K7

Organism

Pongo abelii (Sumatran orangutan)

Taxonomic identifier

9601 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Pongo

Protein attributes

Sequence length	606 AA.
Sequence status	Complete.
Protein existence	Evidence at transcript level

General annotation (Comments)

Function	Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B By similarity.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium By similarity.
Enzyme regulation	Activated by proinflammatory cytokines and in response to physical and chemical stresses, including osmotic stress, oxidative stress, arsenic and ultraviolet light irradiation. Activated by 'Lys-63'-linked polyubiquitination and by autophosphorylation. Association with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 promotes activation through autophosphorylation, whereas PPM1B/PP2CB, PP2A and PPP6C dephosphorylation leads to inactivation By similarity.
Subunit structure	Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts with TAB1/MAP3K7IP1, TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3 By similarity. Identified in the TRIKA2 complex composed of MAP3K7/TAK1, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 By similarity. Interacts with PPM1L and PPM1B/PP2CB By similarity. Interaction with PP2A and PPP6C leads to its repressed activity. Interacts with TRAF6 and TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with TAOK1 and TAOK2; interaction with TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-kappa-B activation By similarity. Interacts with WDR34 (via WD domains) By similarity. Interacts with CYLD and RBCK1 By similarity. Interacts with TGFBR1; induces MAP3K7/TAK1 activation by TRAF6 By similarity. Interacts with MAPK8IP1 and SMAD6 By similarity. Interacts with isoform 1 of VRK2 By similarity.
Subcellular location	Cytoplasm By similarity. Cell membrane; Peripheral membrane protein; Cytoplasmic side By similarity. Note: Although the majority of MAP3K7/TAK1 is found in the cytosol, when complexed with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2, it is also localized at the cell membrane By similarity.
Post-translational modification	Association with TAB1/MAP3K7IP1 promotes autophosphorylation at Ser-192 and subsequent activation. Association with TAB2/MAP3K7IP2, itself associated with free unanchored Lys-63 polyubiquitin chain, promotes autophosphorylation and subsequent activation of MAP3K7. Dephosphorylation at Ser-192 by PPM1B/PP2CB and at Thr-187 by PP2A and PPP6C leads to inactivation By similarity. Ubiquitinated, leading to proteasomal degradation. Requires 'Lys-63'-linked polyubiquitination for autophosphorylation and subsequent activation. 'Lys-63'-linked ubiquitination does not lead to proteasomal degradation. Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains By similarity.
Sequence similarities	Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Apoptosis Stress response Transcription Transcription regulation
Cellular component	Cell membrane Cytoplasm Membrane
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein Ubl conjugation
Gene Ontology (GO)
Biological process	I-kappaB phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of JUN kinase activity Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW MAP kinase kinase kinase activity Inferred from sequence or structural similarity. Source: UniProtKB magnesium ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 606	606	Mitogen-activated protein kinase kinase kinase 7		PRO_0000314285
Regions
	Domain	36 – 291	256	Protein kinase
	Nucleotide binding	42 – 50	9	ATP By similarity
	Region	1 – 300	300	Interaction with MAPK8IP1 By similarity
	Compositional bias	8 – 14	7	Poly-Ser
Sites
	Active site	156	1	Proton acceptor By similarity
	Binding site	63	1	ATP
Amino acid modifications
	Modified residue	184	1	Phosphothreonine; by autocatalysis By similarity
	Modified residue	187	1	Phosphothreonine; by autocatalysis By similarity
	Modified residue	192	1	Phosphoserine; by autocatalysis By similarity
	Modified residue	389	1	Phosphoserine By similarity
	Modified residue	439	1	Phosphoserine By similarity
	Modified residue	444	1	Phosphothreonine By similarity
	Modified residue	455	1	Phosphoserine By similarity

Sequences

	Sequence		Length	Mass (Da)
	Q5RFL3 [UniParc]. Last modified December 21, 2004. Version 1. Checksum: 8024F15A6ADD3CB4	FASTA	606	67,166
	10 20 30 40 50 60 MSTASAASSS SSSSAGEMIE APSQVLNFEE IDYKEIEVEE VVGRGAFGVV CKAKWRAKDV 70 80 90 100 110 120 AIKQIESESE RKAFIVELRQ LSRVNHPNIV KLYGACLNPV CLVMEYAEGG SLYNVLHGAE 130 140 150 160 170 180 PLPYYTAAHA MSWCLQCSQG VAYLHSMQPK ALIHRDLKPP NLLLVAGGTV LKICDFGTAC 190 200 210 220 230 240 DIQTHMTNNK GSAAWMAPEV FEGSNYSEKC DVFSWGIILW EVITRRKPFD EIGGPAFRIM 250 260 270 280 290 300 WAVHNGTRPP LIKNLPKPIE SLMTRCWSKD PSQRPSMEEI VKIMTHLMRY FPGADEPLQY 310 320 330 340 350 360 PCQYSDEGQS NSATSTGSFM DIASTNTSNK SDTNMEQVPA TNDTIKRLES KLLKNQAKQQ 370 380 390 400 410 420 SESGRLSLGA SRGSSVESLP PASEGKRMSA DMSEIEARIA ATTAYSKPKR GHRKTASFGN 430 440 450 460 470 480 ILDVPEIVIS GNGQPRRRSI QDLTVTGTEP GQVSSRSSSP SVRMITTSGP TSEKPTRSHP 490 500 510 520 530 540 WTPDDSTDTN GSDNSIPMAY LTLDHQLQPL APCPNSKESM AVFEQHCKMA QEYMKVQTEI 550 560 570 580 590 600 ALLLQRKQEL VAELDQDEKD QQNTSRLVQE HKKLLDENKS LSTYYQQCKK QLEVIRSQQQ KRQGTS

References

[1]	The German cDNA consortium Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Kidney.

Cross-references

Sequence databases
EMBL GenBank DDBJ	CR857142 mRNA. Translation: CAH89444.1.
RefSeq	NP_001124617.1. NM_001131145.1.
UniGene	Pab.10330.
3D structure databases
HSSP	HSSP built from PDB template 2EVA based on UniProtKB O43318.
ProteinModelPortal	Q5RFL3.
SMR	Q5RFL3. Positions 31-305.
ModBase	Search...
Proteomic databases
PRIDE	Q5RFL3.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	100171454.
KEGG	pon:100171454.
Organism-specific databases
CTD	6885.
Phylogenomic databases
HOVERGEN	HBG003485.
InParanoid	Q5RFL3.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR017421. MAPKKK7. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR001245. Ser-Thr/Tyr_kinase. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
KO	K04427.
Pfam	PF07714. Pkinase_Tyr. 1 hit. [Graphical view]
PIRSF	PIRSF038168. MAPKKK7. 1 hit.
PRINTS	PR00109. TYRKINASE.
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...

Entry information

Entry name

M3K7_PONAB

Accession

Primary (citable) accession number: Q5RFL3

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 15, 2008
Last sequence update:	December 21, 2004
Last modified:	December 14, 2011
This is version 57 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program