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Protein

Mitogen-activated protein kinase kinase kinase 11

Gene

MAP3K11

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Activates the JUN N-terminal pathway. Required for serum-stimulated cell proliferation and for mitogen and cytokine activation of MAPK14 (p38), MAPK3 (ERK) and MAPK8 (JNK1) through phosphorylation and activation of MAP2K4/MKK4 and MAP2K7/MKK7. Plays a role in mitogen-stimulated phosphorylation and activation of BRAF, but does not phosphorylate BRAF directly. Influences microtubule organization during the cell cycle.4 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.1 Publication

Cofactori

Mg2+By similarity

Enzyme regulationi

Homodimerization via the leucine zipper domains is required for autophosphorylation and subsequent activation.2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei144ATPPROSITE-ProRule annotation2 Publications1
Active sitei241Proton acceptorPROSITE-ProRule annotationBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi123 – 131ATPPROSITE-ProRule annotationBy similarity9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • identical protein binding Source: UniProtKB
  • JUN kinase kinase kinase activity Source: UniProtKB
  • mitogen-activated protein kinase kinase binding Source: Ensembl
  • mitogen-activated protein kinase kinase kinase binding Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB
  • protein kinase activity Source: ProtInc
  • protein serine/threonine kinase activity Source: UniProtKB
  • Rac GTPase binding Source: Ensembl

GO - Biological processi

  • activation of JUN kinase activity Source: UniProtKB
  • activation of MAPK activity Source: UniProtKB
  • cell death Source: Ensembl
  • cell proliferation Source: UniProtKB
  • JNK cascade Source: ProtInc
  • microtubule-based process Source: UniProtKB
  • positive regulation of apoptotic process Source: GO_Central
  • positive regulation of JNK cascade Source: UniProtKB
  • positive regulation of JUN kinase activity Source: UniProtKB
  • positive regulation of neuron apoptotic process Source: Ensembl
  • protein autophosphorylation Source: UniProtKB
  • protein phosphorylation Source: UniProtKB

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-HSA-5673000 RAF activation
R-HSA-6802946 Signaling by moderate kinase activity BRAF mutants
R-HSA-6802949 Signaling by RAS mutants
R-HSA-6802955 Paradoxical activation of RAF signaling by kinase inactive BRAF
SignaLinkiQ16584
SIGNORiQ16584

Names & Taxonomyi

Protein namesi
Recommended name:
Mitogen-activated protein kinase kinase kinase 11 (EC:2.7.11.25)
Alternative name(s):
Mixed lineage kinase 3
Src-homology 3 domain-containing proline-rich kinase
Gene namesi
Name:MAP3K11Imported
Synonyms:MLK31 Publication, PTK1, SPRKImported
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

EuPathDBiHostDB:ENSG00000173327.7
HGNCiHGNC:6850 MAP3K11
MIMi600050 gene
neXtProtiNX_Q16584

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Cytoskeleton

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi144K → A: Greatly reduced autophosphorylation activity. 2 Publications1
Mutagenesisi144K → R: Loss of kinase activity. Prevents activation of SAPK and MAPK14. 2 Publications1
Mutagenesisi164E → A: Greatly reduced autophosphorylation activity. 1 Publication1
Mutagenesisi277T → A: Severely reduced autophosphorylation activity. Prevents phosphorylation of SAPK and MAPK14. 1 Publication1
Mutagenesisi277T → E: No effect on SAPK activation. 1 Publication1
Mutagenesisi278T → A: No effect on autophosphorylation activity or activation of SAPK and MAPK14. 1 Publication1
Mutagenesisi281S → A: Reduced autophosphorylation activity. Reduced activation of SAPK and MAPK14. 1 Publication1
Mutagenesisi281S → E: No effect on SAPK activation. 1 Publication1

Organism-specific databases

DisGeNETi4296
OpenTargetsiENSG00000173327
PharmGKBiPA30594

Chemistry databases

ChEMBLiCHEMBL2708
GuidetoPHARMACOLOGYi2071

Polymorphism and mutation databases

BioMutaiMAP3K11
DMDMi71153819

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000862601 – 847Mitogen-activated protein kinase kinase kinase 11Add BLAST847

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei11PhosphoserineCombined sources1
Modified residuei35PhosphoserineBy similarity1
Modified residuei277Phosphothreonine; by autocatalysis1 Publication1
Modified residuei281Phosphoserine; by autocatalysis and MAP4K11 Publication1
Modified residuei394PhosphoserineCombined sources1
Modified residuei507PhosphoserineCombined sources1
Modified residuei524PhosphoserineCombined sources1 Publication1
Modified residuei548PhosphoserineCombined sources1
Modified residuei555Phosphoserine1 Publication1
Modified residuei556Phosphoserine1 Publication1
Modified residuei654Phosphoserine1 Publication1
Modified residuei693PhosphoserineCombined sources1
Modified residuei705PhosphoserineCombined sources1 Publication1
Modified residuei708PhosphothreonineCombined sources1
Modified residuei724Phosphoserine1 Publication1
Modified residuei727Phosphoserine1 Publication1
Modified residuei740Phosphoserine1 Publication1
Modified residuei748PhosphoserineCombined sources1
Modified residuei758PhosphoserineCombined sources1 Publication1
Modified residuei770Phosphoserine1 Publication1
Modified residuei789PhosphoserineCombined sources1
Modified residuei793PhosphoserineCombined sources1 Publication1
Modified residuei815PhosphoserineCombined sources1

Post-translational modificationi

Autophosphorylation on serine and threonine residues within the activation loop plays a role in enzyme activation. Thr-277 is likely to be the main autophosphorylation site. Phosphorylation of Ser-555 and Ser-556 is induced by CDC42.3 Publications

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ16584
MaxQBiQ16584
PaxDbiQ16584
PeptideAtlasiQ16584
PRIDEiQ16584
ProteomicsDBi60929

PTM databases

iPTMnetiQ16584
PhosphoSitePlusiQ16584

Expressioni

Tissue specificityi

Expressed in a wide variety of normal and neoplastic tissues including fetal lung, liver, heart and kidney, and adult lung, liver, heart, kidney, placenta, skeletal muscle, pancreas and brain.2 Publications

Gene expression databases

BgeeiENSG00000173327
CleanExiHS_MAP3K11
ExpressionAtlasiQ16584 baseline and differential
GenevisibleiQ16584 HS

Organism-specific databases

HPAiCAB010165

Interactioni

Subunit structurei

Homodimer; undergoes dimerization during activation. Interacts with MAP2K4/MKK4. Interacts with MAP2K7/MKK7 (By similarity).By similarity

Binary interactionsi

Show more details

GO - Molecular functioni

  • identical protein binding Source: UniProtKB
  • mitogen-activated protein kinase kinase binding Source: Ensembl
  • mitogen-activated protein kinase kinase kinase binding Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB
  • Rac GTPase binding Source: Ensembl

Protein-protein interaction databases

BioGridi110442, 37 interactors
CORUMiQ16584
IntActiQ16584, 18 interactors
MINTiQ16584
STRINGi9606.ENSP00000309597

Chemistry databases

BindingDBiQ16584

Structurei

Secondary structure

1847
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi45 – 50Combined sources6
Beta strandi67 – 73Combined sources7
Helixi78 – 80Combined sources3
Beta strandi83 – 88Combined sources6
Beta strandi91 – 96Combined sources6
Helixi97 – 99Combined sources3
Beta strandi100 – 105Combined sources6

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5K26X-ray1.20A/B41-105[»]
5K28X-ray1.50A/B44-105[»]
ProteinModelPortaliQ16584
SMRiQ16584
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini41 – 105SH3PROSITE-ProRule annotationAdd BLAST65
Domaini117 – 379Protein kinasePROSITE-ProRule annotationAdd BLAST263

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni403 – 424Leucine-zipper 1Add BLAST22
Regioni438 – 459Leucine-zipper 2Add BLAST22

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi14 – 138Gly-richSequence analysisAdd BLAST125
Compositional biasi18 – 30Poly-GlySequence analysisAdd BLAST13
Compositional biasi426 – 514Arg-richSequence analysisAdd BLAST89
Compositional biasi599 – 825Pro-richSequence analysisAdd BLAST227

Sequence similaritiesi

Keywords - Domaini

Repeat, SH3 domain

Phylogenomic databases

eggNOGiKOG0192 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00900000140790
HOGENOMiHOG000060081
HOVERGENiHBG067662
InParanoidiQ16584
KOiK04419
OMAiYANPVWT
OrthoDBiEOG091G0JNI
PhylomeDBiQ16584
TreeFamiTF105118

Family and domain databases

CDDicd12059 SH3_MLK1-3, 1 hit
InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR035779 MLK1-3_SH3
IPR016231 MLK1-4
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR008271 Ser/Thr_kinase_AS
IPR036028 SH3-like_dom_sf
IPR001452 SH3_domain
PfamiView protein in Pfam
PF07714 Pkinase_Tyr, 1 hit
PF14604 SH3_9, 1 hit
PIRSFiPIRSF000556 MAPKKK9_11, 1 hit
PRINTSiPR00452 SH3DOMAIN
PR00109 TYRKINASE
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SM00326 SH3, 1 hit
SUPFAMiSSF50044 SSF50044, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit
PS50002 SH3, 1 hit

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q16584-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MEPLKSLFLK SPLGSWNGSG SGGGGGGGGG RPEGSPKAAG YANPVWTALF
60 70 80 90 100
DYEPSGQDEL ALRKGDRVEV LSRDAAISGD EGWWAGQVGG QVGIFPSNYV
110 120 130 140 150
SRGGGPPPCE VASFQELRLE EVIGIGGFGK VYRGSWRGEL VAVKAARQDP
160 170 180 190 200
DEDISVTAES VRQEARLFAM LAHPNIIALK AVCLEEPNLC LVMEYAAGGP
210 220 230 240 250
LSRALAGRRV PPHVLVNWAV QIARGMHYLH CEALVPVIHR DLKSNNILLL
260 270 280 290 300
QPIESDDMEH KTLKITDFGL AREWHKTTQM SAAGTYAWMA PEVIKASTFS
310 320 330 340 350
KGSDVWSFGV LLWELLTGEV PYRGIDCLAV AYGVAVNKLT LPIPSTCPEP
360 370 380 390 400
FAQLMADCWA QDPHRRPDFA SILQQLEALE AQVLREMPRD SFHSMQEGWK
410 420 430 440 450
REIQGLFDEL RAKEKELLSR EEELTRAARE QRSQAEQLRR REHLLAQWEL
460 470 480 490 500
EVFERELTLL LQQVDRERPH VRRRRGTFKR SKLRARDGGE RISMPLDFKH
510 520 530 540 550
RITVQASPGL DRRRNVFEVG PGDSPTFPRF RAIQLEPAEP GQAWGRQSPR
560 570 580 590 600
RLEDSSNGER RACWAWGPSS PKPGEAQNGR RRSRMDEATW YLDSDDSSPL
610 620 630 640 650
GSPSTPPALN GNPPRPSLEP EEPKRPVPAE RGSSSGTPKL IQRALLRGTA
660 670 680 690 700
LLASLGLGRD LQPPGGPGRE RGESPTTPPT PTPAPCPTEP PPSPLICFSL
710 720 730 740 750
KTPDSPPTPA PLLLDLGIPV GQRSAKSPRR EEEPRGGTVS PPPGTSRSAP
760 770 780 790 800
GTPGTPRSPP LGLISRPRPS PLRSRIDPWS FVSAGPRPSP LPSPQPAPRR
810 820 830 840
APWTLFPDSD PFWDSPPANP FQGGPQDCRA QTKDMGAQAP WVPEAGP
Length:847
Mass (Da):92,688
Last modified:November 1, 1996 - v1
Checksum:iAFB6E930EA281C15
GO
Isoform 2 (identifier: Q16584-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-257: Missing.

Note: No experimental confirmation available.
Show »
Length:590
Mass (Da):65,344
Checksum:iC7C24CA0C053133D
GO

Sequence cautioni

The sequence BAD92892 differs from that shown. Reason: Erroneous initiation.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti247 – 272ILLLQ…FGLAR → SEFLGAWLGVAWLWYTPAPN LPLSLA in BAD92892 (Ref. 4) CuratedAdd BLAST26
Sequence conflicti791L → P in BAD96501 (Ref. 4) Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_040703151D → V1 PublicationCorresponds to variant dbSNP:rs34178129Ensembl.1
Natural variantiVAR_030604252P → H1 PublicationCorresponds to variant dbSNP:rs17855912Ensembl.1
Natural variantiVAR_040704282A → G1 PublicationCorresponds to variant dbSNP:rs34594252Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0561831 – 257Missing in isoform 2. 1 PublicationAdd BLAST257

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U07747 mRNA Translation: AAA19647.1
L32976 mRNA Translation: AAA59859.1
AB209655 mRNA Translation: BAD92892.1 Different initiation.
AK299609 mRNA Translation: BAG61538.1
AK316032 mRNA Translation: BAH14403.1
AK222781 mRNA Translation: BAD96501.1
AP001362 Genomic DNA No translation available.
BC011263 mRNA Translation: AAH11263.1
BC064543 mRNA Translation: AAH64543.1
CCDSiCCDS8107.1 [Q16584-1]
PIRiA53800
RefSeqiNP_002410.1, NM_002419.3 [Q16584-1]
UniGeneiHs.502872

Genome annotation databases

EnsembliENST00000309100; ENSP00000309597; ENSG00000173327 [Q16584-1]
ENST00000530153; ENSP00000433886; ENSG00000173327 [Q16584-2]
GeneIDi4296
KEGGihsa:4296
UCSCiuc001oew.4 human [Q16584-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiM3K11_HUMAN
AccessioniPrimary (citable) accession number: Q16584
Secondary accession number(s): B4DS76
, Q53H00, Q59F06, Q6P2G4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 19, 2005
Last sequence update: November 1, 1996
Last modified: June 20, 2018
This is version 175 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

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