Q16584 (M3K11_HUMAN) Reviewed, UniProtKB/Swiss-Prot

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) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	847 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

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) 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. Ref.1 Ref.5 Ref.9 Ref.10
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.6 Ref.7
Subunit structure	Homodimer; undergoes dimerization during activation. Interacts with MAP2K4/MKK4. Interacts with MAP2K7/MKK7 By similarity. Ref.5 Ref.6
Subcellular location	Cytoplasm › cytoskeleton › centrosome. Note: Location is cell cycle dependent. Ref.9
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.7 Ref.8
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.
Sequence caution	The sequence BAD92892.1 differs from that shown. Reason: Erroneous initiation.

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 Reference proteome
Gene Ontology (GO)
Biological_process	G1 phase of mitotic cell cycle Inferred from mutant phenotype Ref.10. Source: UniProtKB activation of JUN kinase activity Inferred from mutant phenotype Ref.10. Source: UniProtKB cell death Inferred from electronic annotation. Source: Compara cell proliferation Inferred from mutant phenotype Ref.10. Source: UniProtKB microtubule-based process Inferred from mutant phenotype Ref.9. Source: UniProtKB positive regulation of JNK cascade Inferred from mutant phenotype PubMed 17584736. Source: UniProtKB positive regulation of neuron apoptotic process Inferred from electronic annotation. Source: Compara protein autophosphorylation Inferred from direct assay Ref.1. Source: UniProtKB
Cellular_component	centrosome Inferred from direct assay Ref.9. Source: UniProtKB cytoplasm Inferred from electronic annotation. Source: UniProtKB-KW microtubule Inferred from direct assay Ref.9. 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 tyrosine kinase activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CDC42	P60953	2	EBI-49961,EBI-81752
NF2	P35240	4	EBI-49961,EBI-1014472

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	65	SH3
	Domain	117 – 379	263	Protein kinase
	Nucleotide binding	123 – 131	9	ATP By similarity UniProtKB Q02779
	Region	403 – 424	22	Leucine-zipper 1
	Region	438 – 459	22	Leucine-zipper 2
	Compositional bias	14 – 138	125	Gly-rich
	Compositional bias	18 – 30	13	Poly-Gly
	Compositional bias	426 – 514	89	Arg-rich
	Compositional bias	599 – 825	227	Pro-rich
Sites
	Active site	241	1	Proton acceptor By similarity UniProtKB Q02779
	Binding site	144	1	ATP Ref.1 Ref.7
Amino acid modifications
	Modified residue	11	1	Phosphoserine Ref.12
	Modified residue	277	1	Phosphothreonine; by autocatalysis Ref.7
	Modified residue	281	1	Phosphoserine; by autocatalysis and MAP4K1 Ref.7
	Modified residue	394	1	Phosphoserine Ref.14
	Modified residue	507	1	Phosphoserine Ref.11 Ref.12 Ref.14
	Modified residue	524	1	Phosphoserine Ref.8
	Modified residue	548	1	Phosphoserine Ref.12 Ref.14
	Modified residue	555	1	Phosphoserine Ref.8
	Modified residue	556	1	Phosphoserine Ref.8
	Modified residue	654	1	Phosphoserine Ref.8
	Modified residue	693	1	Phosphoserine Ref.14
	Modified residue	705	1	Phosphoserine Ref.8 Ref.12 Ref.14
	Modified residue	708	1	Phosphothreonine Ref.12
	Modified residue	724	1	Phosphoserine Ref.8
	Modified residue	727	1	Phosphoserine Ref.8
	Modified residue	740	1	Phosphoserine Ref.8
	Modified residue	748	1	Phosphoserine Ref.12 Ref.14
	Modified residue	758	1	Phosphoserine Ref.8 Ref.12 Ref.14
	Modified residue	770	1	Phosphoserine Ref.8
	Modified residue	789	1	Phosphoserine Ref.13 Ref.14 Ref.15
	Modified residue	793	1	Phosphoserine Ref.8 Ref.12 Ref.13 Ref.14 Ref.15
	Modified residue	815	1	Phosphoserine Ref.12
Natural variations
	Natural variant	151	1	D → V. Ref.16 Corresponds to variant rs34178129 [ dbSNP | Ensembl ].		VAR_040703
	Natural variant	252	1	P → H. Ref.4 Corresponds to variant rs17855912 [ dbSNP | Ensembl ].		VAR_030604
	Natural variant	282	1	A → G. Ref.16 Corresponds to variant rs34594252 [ dbSNP | Ensembl ].		VAR_040704
Experimental info
	Mutagenesis	144	1	K → A: Greatly reduced autophosphorylation activity. Ref.1 Ref.7
	Mutagenesis	144	1	K → R: Loss of kinase activity. Prevents activation of SAPK and MAPK14. Ref.1 Ref.7
	Mutagenesis	164	1	E → A: Greatly reduced autophosphorylation activity. Ref.1
	Mutagenesis	277	1	T → A: Severely reduced autophosphorylation activity. Prevents phosphorylation of SAPK and MAPK14. Ref.7
	Mutagenesis	277	1	T → E: No effect on SAPK activation. Ref.7
	Mutagenesis	278	1	T → A: No effect on autophosphorylation activity or activation of SAPK and MAPK14. Ref.7
	Mutagenesis	281	1	S → A: Reduced autophosphorylation activity. Reduced activation of SAPK and MAPK14. Ref.7
	Mutagenesis	281	1	S → E: No effect on SAPK activation. Ref.7
	Sequence conflict	247 – 272	26	ILLLQ…FGLAR → SEFLGAWLGVAWLWYTPAPN LPLSLA in BAD92892. Ref.3
	Sequence conflict	791	1	L → P in BAD96501. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Q16584 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: AFB6E930EA281C15	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

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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT HIS-252. Tissue: Brain and Hippocampus.
[5]	"MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6." Tibbles L.A., Ing Y.L., Kiefer F., Chan J., Iscove N., Woodgett J.R., Lassam N.J. EMBO J. 15:7026-7035(1996) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MAP2K4/MKK4, FUNCTION IN PHOSPHORYLATION OF MAP2K4/MKK4.
[6]	"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] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION, HOMODIMERIZATION.
[7]	"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] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION, PHOSPHORYLATION AT THR-277 AND SER-281, MUTAGENESIS OF LYS-144; THR-277; THR-278 AND SER-281.
[8]	"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] [Europe PMC] [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.
[9]	"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] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[10]	"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] [Europe PMC] [Abstract] Cited for: FUNCTION.
[11]	"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] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-507, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[12]	"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] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-11; SER-507; SER-548; SER-705; THR-708; SER-748; SER-758; SER-793 AND SER-815, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[13]	"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] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-789 AND SER-793, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[14]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-394; SER-507; SER-548; SER-693; SER-705; SER-748; SER-758; SER-789 AND SER-793, MASS SPECTROMETRY.
[15]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-789 AND SER-793, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[16]	"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. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] VAL-151 AND GLY-282.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	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. NM_002419.3.
UniGene	Hs.502872.
3D structure databases
ProteinModelPortal	Q16584.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q16584. 9 interactions.
MINT	MINT-2836851.
STRING	9606.ENSP00000309597.
PTM databases
PhosphoSite	Q16584.
Polymorphism databases
DMDM	71153819.
Proteomic databases
PaxDb	Q16584.
PRIDE	Q16584.
Protocols and materials databases
DNASU	4296.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000309100; ENSP00000309597; ENSG00000173327.
GeneID	4296.
KEGG	hsa:4296.
UCSC	uc001oew.3. human.
Organism-specific databases
CTD	4296.
GeneCards	GC11M065365.
HGNC	HGNC:6850. MAP3K11.
HPA	CAB010165.
MIM	600050. gene.
neXtProt	NX_Q16584.
PharmGKB	PA30594.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000060081.
HOVERGEN	HBG067662.
InParanoid	Q16584.
KO	K04419.
OMA	SGTPKLI.
OrthoDB	EOG4PNXGN.
PhylomeDB	Q16584.
Enzyme and pathway databases
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	IPR011009. Kinase-like_dom. IPR016231. MAPKKK9/10/11. IPR015785. MAPKKK9/10/11-like. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR001245. Ser-Thr/Tyr_kinase_cat_dom. IPR008271. Ser/Thr_kinase_AS. IPR011511. SH3_2. IPR001452. SH3_domain. IPR020635. Tyr_kinase_cat_dom. [Graphical view]
PANTHER	PTHR23257:SF87. PTHR23257:SF87. 1 hit.
Pfam	PF07714. Pkinase_Tyr. 1 hit. PF07653. SH3_2. 1 hit. [Graphical view]
PIRSF	PIRSF000556. MAPKKK9_11. 1 hit.
PRINTS	PR00452. SH3DOMAIN. PR00109. TYRKINASE.
SMART	SM00326. SH3. 1 hit. SM00219. TyrKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit. SSF50044. SH3. 1 hit.
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
BindingDB	Q16584.
ChEMBL	CHEMBL2708.
GenomeRNAi	4296.
NextBio	16911.
SOURCE	Search...

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:	May 1, 2013
This is version 128 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

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.