Mitogen-activated protein kinase kinase kinase 11

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Reviewed, UniProtKB/Swiss-Prot Q16584 (M3K11_HUMAN)

Last modified November 3, 2009. Version 90. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

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 names

Name:	MAP3K11
Synonyms:	MLK3, PTK1, SPRK

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

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Protein attributes

Sequence length	847 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	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). Plays a role in mitogen-stimulated phosphorylation and activation of BRAF, but does not phosphorylate BRAF directly. Influences microtubule organization during the cell cycle. Ref.1 Ref.8 Ref.9
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. Ref.1
Cofactor	Magnesium By similarity. UniProtKB P80192
Enzyme regulation	Homodimerization via the leucine zipper domains is required for autophosphorylation and subsequent activation. Ref.5 Ref.6
Subunit structure	Homodimer; undergoes dimerization during activation. Ref.5
Subcellular location	Cytoplasm › cytoskeleton › centrosome. Note: Location is cell cycle dependent. Ref.8
Tissue specificity	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. Ref.1 Ref.2
Post-translational modification	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. Ref.1 Ref.6 Ref.7
Sequence similarities	Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. Contains 1 protein kinase domain. Contains 1 SH3 domain.

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Ontologies

Keywords
Cellular component	Cytoplasm Cytoskeleton
Coding sequence diversity	Polymorphism
Domain	Repeat SH3 domain
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	G1 phase of mitotic cell cycle Ref.9 Inferred from mutant phenotype. Source: UniProtKB activation of JUN kinase activity Ref.9 Inferred from mutant phenotype. Source: UniProtKB cell proliferation Ref.9 Inferred from mutant phenotype. Source: UniProtKB microtubule-based process Ref.8 Inferred from mutant phenotype. Source: UniProtKB protein amino acid autophosphorylation Ref.1 Inferred from direct assay. Source: UniProtKB protein oligomerization Ref.5 Inferred from physical interaction. Source: UniProtKB
Cellular component	centrosome Ref.8 Inferred from direct assay. Source: UniProtKB microtubule Ref.8 Inferred from direct assay. Source: UniProtKB
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW JUN kinase kinase kinase activity Inferred from sequence or structural similarity. Source: UniProtKB protein homodimerization activity Ref.5 Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

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Binary interactions

With	Entry	#Exp.	IntAct	Notes
GSK3A	P49840	1	EBI-49961,EBI-1044067
MAP4K2	Q12851	1	EBI-49961,EBI-49783

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 847

847

Mitogen-activated protein kinase kinase kinase 11

PRO_0000086260

Regions

Domain

41 – 105

SH3

Domain

117 – 379

263

Protein kinase

Domain

403 – 424

Leucine-zipper 1 By similarity UniProtKB Q02779

Domain

438 – 459

Leucine-zipper 2 By similarity UniProtKB Q02779

Nucleotide binding

123 – 131

ATP By similarity UniProtKB Q02779

Compositional bias

14 – 138

125

Gly-rich

Compositional bias

18 – 30

Poly-Gly

Compositional bias

426 – 514

Arg-rich

Compositional bias

599 – 825

227

Pro-rich

Sites

Active site

241

Proton acceptor By similarity UniProtKB Q02779

Binding site

144

ATP Ref.1 Ref.6

Amino acid modifications

Modified residue

Phosphoserine Ref.13

Modified residue

277

Phosphothreonine; by autocatalysis Ref.6

Modified residue

281

Phosphoserine; by autocatalysis and MAP4K1 Ref.6

Modified residue

493

Phosphoserine Ref.13

Modified residue

507

Phosphoserine Ref.13 Ref.10

Modified residue

524

Phosphoserine Ref.13 Ref.7 Ref.12

Modified residue

548

Phosphoserine Ref.13

Modified residue

555

Phosphoserine Ref.7

Modified residue

556

Phosphoserine Ref.7

Modified residue

654

Phosphoserine Ref.7

Modified residue

705

Phosphoserine Ref.13 Ref.7

Modified residue

708

Phosphothreonine Ref.13

Modified residue

724

Phosphoserine Ref.7

Modified residue

727

Phosphoserine Ref.7

Modified residue

738

Phosphothreonine Ref.13 Ref.11

Modified residue

740

Phosphoserine Ref.13 Ref.7 Ref.11

Modified residue

746

Phosphoserine Ref.11

Modified residue

748

Phosphoserine Ref.13

Modified residue

752

Phosphothreonine Ref.13

Modified residue

755

Phosphothreonine Ref.13

Modified residue

758

Phosphoserine Ref.13 Ref.7

Modified residue

770

Phosphoserine Ref.7

Modified residue

789

Phosphoserine Ref.14

Modified residue

793

Phosphoserine Ref.13 Ref.7 Ref.14

Modified residue

815

Phosphoserine Ref.13

Natural variations

Natural variant

151

D → V: dbSNP rs34178129. Ref.15

VAR_040703

Natural variant

252

P → H: dbSNP rs17855912. Ref.4

VAR_030604

Natural variant

282

A → G: dbSNP rs34594252. Ref.15

VAR_040704

Experimental info

Mutagenesis

144

K → A: Greatly reduced autophosphorylation activity. Ref.1 Ref.6

Mutagenesis

144

K → R: Loss of kinase activity. Prevents activation of SAPK and MAPK14. Ref.1 Ref.6

Mutagenesis

164

E → A: Greatly reduced autophosphorylation activity. Ref.1

Mutagenesis

277

T → A: Severely reduced autophosphorylation activity. Prevents phosphorylation of SAPK and MAPK14. Ref.6

Mutagenesis

277

T → E: No effect on SAPK activation. Ref.6

Mutagenesis

278

T → A: No effect on autophosphorylation activity or activation of SAPK and MAPK14. Ref.6

Mutagenesis

281

S → A: Reduced autophosphorylation activity. Reduced activation of SAPK and MAPK14. Ref.6

Mutagenesis

281

S → E: No effect on SAPK activation. Ref.6

Sequence conflict

247 – 272

ILLLQ…FGLAR → SEFLGAWLGVAWLWYTPAPN LPLSLA in BAD92892. Ref.3

Sequence conflict

791

L → P in BAD96501. Ref.3

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Sequences

Sequence

Length

Mass (Da)

Tools

Q16584-1 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: AFB6E930EA281C15
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FASTA

847

92,688

        10         20         30         40         50         60 
MEPLKSLFLK SPLGSWNGSG SGGGGGGGGG RPEGSPKAAG YANPVWTALF DYEPSGQDEL 

        70         80         90        100        110        120 
ALRKGDRVEV LSRDAAISGD EGWWAGQVGG QVGIFPSNYV SRGGGPPPCE VASFQELRLE 

       130        140        150        160        170        180 
EVIGIGGFGK VYRGSWRGEL VAVKAARQDP DEDISVTAES VRQEARLFAM LAHPNIIALK 

       190        200        210        220        230        240 
AVCLEEPNLC LVMEYAAGGP LSRALAGRRV PPHVLVNWAV QIARGMHYLH CEALVPVIHR 

       250        260        270        280        290        300 
DLKSNNILLL QPIESDDMEH KTLKITDFGL AREWHKTTQM SAAGTYAWMA PEVIKASTFS 

       310        320        330        340        350        360 
KGSDVWSFGV LLWELLTGEV PYRGIDCLAV AYGVAVNKLT LPIPSTCPEP FAQLMADCWA 

       370        380        390        400        410        420 
QDPHRRPDFA SILQQLEALE AQVLREMPRD SFHSMQEGWK REIQGLFDEL RAKEKELLSR 

       430        440        450        460        470        480 
EEELTRAARE QRSQAEQLRR REHLLAQWEL EVFERELTLL LQQVDRERPH VRRRRGTFKR 

       490        500        510        520        530        540 
SKLRARDGGE RISMPLDFKH RITVQASPGL DRRRNVFEVG PGDSPTFPRF RAIQLEPAEP 

       550        560        570        580        590        600 
GQAWGRQSPR RLEDSSNGER RACWAWGPSS PKPGEAQNGR RRSRMDEATW YLDSDDSSPL 

       610        620        630        640        650        660 
GSPSTPPALN GNPPRPSLEP EEPKRPVPAE RGSSSGTPKL IQRALLRGTA LLASLGLGRD 

       670        680        690        700        710        720 
LQPPGGPGRE RGESPTTPPT PTPAPCPTEP PPSPLICFSL KTPDSPPTPA PLLLDLGIPV 

       730        740        750        760        770        780 
GQRSAKSPRR EEEPRGGTVS PPPGTSRSAP GTPGTPRSPP LGLISRPRPS PLRSRIDPWS 

       790        800        810        820        830        840 
FVSAGPRPSP LPSPQPAPRR APWTLFPDSD PFWDSPPANP FQGGPQDCRA QTKDMGAQAP 


WVPEAGP

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification and characterization of SPRK, a novel src-homology 3 domain-containing proline-rich kinase with serine/threonine kinase activity." Gallo K.A., Mark M.R., Scadden D.T., Wang Z., Gu Q., Godowski P.J. J. Biol. Chem. 269:15092-15100(1994) [PubMed: 8195146] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, TISSUE SPECIFICITY, AUTOPHOSPHORYLATION, MUTAGENESIS OF LYS-144 AND GLU-164. Tissue: Megakaryocyte.
[2]	"MLK-3: identification of a widely-expressed protein kinase bearing an SH3 domain and a leucine zipper-basic region domain." Ing Y.L., Leung I.W.L., Heng H.H.Q., Tsui L.-C., Lassam N.J. Oncogene 9:1745-1750(1994) [PubMed: 8183572] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY. Tissue: Thymus.
[3]	Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Liver and Spleen.
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT HIS-252. Tissue: Brain and Hippocampus.
[5]	"Dimerization via tandem leucine zippers is essential for the activation of the mitogen-activated protein kinase kinase kinase, MLK-3." Leung I.W.L., Lassam N.J. J. Biol. Chem. 273:32408-32415(1998) [PubMed: 9829970] [Abstract] Cited for: ENZYME REGULATION, HOMODIMERIZATION.
[6]	"The kinase activation loop is the key to mixed lineage kinase-3 activation via both autophosphorylation and hematopoietic progenitor kinase 1 phosphorylation." Leung I.W.L., Lassam N.J. J. Biol. Chem. 276:1961-1967(2001) [PubMed: 11053428] [Abstract] Cited for: ENZYME REGULATION, PHOSPHORYLATION AT THR-277 AND SER-281, MUTAGENESIS OF LYS-144; THR-277; THR-278 AND SER-281.
[7]	"Identification of in vivo phosphorylation sites of MLK3 by mass spectrometry and phosphopeptide mapping." Vacratsis P.O., Phinney B.S., Gage D.A., Gallo K.A. Biochemistry 41:5613-5624(2002) [PubMed: 11969422] [Abstract] Cited for: PHOSPHORYLATION AT SER-524; SER-555; SER-556; SER-654; SER-705; SER-724; SER-727; SER-740; SER-758; SER-770 AND SER-793.
[8]	"A new identity for MLK3 as an NIMA-related, cell cycle-regulated kinase that is localized near centrosomes and influences microtubule organization." Swenson K.I., Winkler K.E., Means A.R. Mol. Biol. Cell 14:156-172(2003) [PubMed: 12529434] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[9]	"MLK3 is required for mitogen activation of B-Raf, ERK and cell proliferation." Chadee D.N., Kyriakis J.M. Nat. Cell Biol. 6:770-776(2004) [PubMed: 15258589] [Abstract] Cited for: FUNCTION.
[10]	"A probability-based approach for high-throughput protein phosphorylation analysis and site localization." Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P. Nat. Biotechnol. 24:1285-1292(2006) [PubMed: 16964243] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-507, MASS SPECTROMETRY. Tissue: Epithelium.
[11]	"Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra." Yu L.-R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D. J. Proteome Res. 6:4150-4162(2007) [PubMed: 17924679] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-738; SER-740 AND SER-746, MASS SPECTROMETRY. Tissue: Epithelium.
[12]	"Proteomics analysis of protein kinases by target class-selective prefractionation and tandem mass spectrometry." Wissing J., Jaensch L., Nimtz M., Dieterich G., Hornberger R., Keri G., Wehland J., Daub H. Mol. Cell. Proteomics 6:537-547(2007) [PubMed: 17192257] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-524, MASS SPECTROMETRY.
[13]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-35; SER-493; SER-507; SER-524; SER-548; SER-705; THR-708; THR-738; SER-740; SER-748; THR-752; THR-755; SER-758; SER-793 AND SER-815, MASS SPECTROMETRY.
[14]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-789 AND SER-793, MASS SPECTROMETRY.
[15]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] VAL-151 AND GLY-282.
+	Additional computationally mapped references.

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Cross-references

Sequence databases
	U07747 mRNA. Translation: AAA19647.1. L32976 mRNA. Translation: AAA59859.1. AB209655 mRNA. Translation: BAD92892.1. Different initiation. AK222781 mRNA. Translation: BAD96501.1. BC011263 mRNA. Translation: AAH11263.1. BC064543 mRNA. Translation: AAH64543.1.
IPI	IPI00000977.
PIR	A53800.
RefSeq	NP_002410.1.
UniGene	Hs.502872
3D structure databases
HSSP	HSSP built from PDB template 1R1W based on UniProtKB P08581.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q16584. 6 interactions.
STRING	Q16584.
PTM databases
PhosphoSite	Q16584.
Proteomic databases
PRIDE	Q16584.
Genome annotation databases
Ensembl	ENST00000309100; ENSP00000309597; ENSG00000173327; Homo sapiens. [Genome view]
GeneID	4296.
KEGG	hsa:4296.
UCSC	uc001oew.1. human.
Organism-specific databases
CTD	4296.
GeneCards	GC11M065121.
H-InvDB	HIX0009802.
HGNC	HGNC:6850. MAP3K11.
MIM	600050. gene.
PharmGKB	PA30594.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	Q16584.
HOVERGEN	Q16584.
OMA	QVGIFPS.
Enzyme and pathway databases
BRENDA	2.7.11.25. 247.
Pathway_Interaction_DB	ifngpathway. IFN-gamma pathway. reelinpathway. Reelin signaling pathway.
Gene expression databases
ArrayExpress	Q16584.
Bgee	Q16584.
CleanEx	HS_MAP3K11.
Genevestigator	Q16584.
GermOnline	ENSG00000173327. Homo sapiens.
Family and domain databases
InterPro	IPR015785. MAPKKK-like. IPR016231. MAPKKK9/10/11. IPR000719. Prot_kinase_core. IPR017441. Protein_kinase_ATP_BS. IPR017442. Se/Thr_pkinase-rel. IPR008271. Ser_thr_pkin_AS. IPR001452. SH3_domain. IPR020473. SH3_region. IPR001245. Tyr_pkinase. [Graphical view]
PANTHER	PTHR23257:SF87. MAPKKK-like. 1 hit.
Pfam	PF00069. Pkinase. 1 hit. PF00018. SH3_1. 1 hit. [Graphical view]
PIRSF	PIRSF000556. MAPKKK9_11. 1 hit.
PRINTS	PR00452. SH3DOMAIN. PR00109. TYRKINASE.
ProDom	PD000001. Prot_kinase. 1 hit. PD000066. SH3. 1 hit. [Graphical view] [Entries sharing at least one domain]
SMART	SM00326. SH3. 1 hit. SM00219. TyrKc. 1 hit. [Graphical view]
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. PS50002. SH3. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
BindingDB	Q16584.
NextBio	16911.
SOURCE	Search...

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Entry information

Entry name

M3K11_HUMAN

Accession

Primary (citable) accession number: Q16584
Secondary accession number(s): Q53H00, Q59F06, Q6P2G4

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 19, 2005
Last sequence update:	November 1, 1996
Last modified:	November 3, 2009
This is version 90 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any 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.

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SIMILARITY comments

Index of protein domains and families

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Natural variations

Experimental info

Sequences

References

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

Proteomic databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Gene expression databases

Family and domain databases

Other Resources

Entry information

Relevant documents