Reviewed, UniProtKB/Swiss-Prot O54949 (NLK_MOUSE)

Names and origin

Protein names

Recommended name:
    Serine/threonine protein kinase NLK
    EC=2.7.11.24
Alternative name(s):
    Nemo-like kinase

Gene names

Name:

Nlk

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	527 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Role in cell fate determination, required for differentiation of bone marrow stromal cells. Acts downstream of MAP3K7 and HIPK2 to negatively regulate the canonical Wnt/beta-catenin signaling pathway and the phosphorylation and destruction of the MYB transcription factor. May suppress a wide range of transcription factors by phosphorylation of the coactivator, CREBBP. Involved in TGFbeta-mediated mesoderm induction, acting downstream of MAP3K7/TAK1 to phosphorylate STAT3. Ref.1 Ref.4 Ref.5 Ref.6 Ref.7 Ref.8
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. Ref.6 Ref.8
Cofactor	Magnesium. Ref.1 Ref.5
Enzyme regulation	Activated by tyrosine and threonine phosphorylation. Activated by activin By similarity. Ref.7
Subunit structure	Interacts with RNF138/NARF and TCF7L2/TCF4 By similarity. Interacts with STAT3. Interacts with HIPK2 and MYB.
Subcellular location	Nucleus. Cytoplasm. Note: Predominantly nuclear. A smaller fraction is cytoplasmic. Ref.1
Tissue specificity	Expressed at high levels in the brain, and at lower levels in heart, kidney, lung and liver. Ref.1
Domain	The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.
Post-translational modification	Dually phosphorylated on Thr-303 and Tyr-305, which activates the enzyme By similarity.
Sequence similarities	Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. Contains 1 protein kinase domain.
Sequence caution	The sequence AAC24499.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

Ontologies

Keywords
Biological process	Transcription Transcription regulation Wnt signaling pathway
Cellular component	Cytoplasm Nucleus
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Gene Ontology (GO)
Biological process	Wnt receptor signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of Wnt receptor signaling pathway Ref.7 Inferred from mutant phenotype. Source: UniProtKB peptidyl-threonine phosphorylation Ref.8 Inferred from direct assay. Source: UniProtKB protein amino acid autophosphorylation Ref.1 Inferred from direct assay. Source: MGI regulation of transcription Ref.5 Inferred from mutant phenotype. Source: UniProtKB serine phosphorylation of STAT3 protein Ref.6 Inferred from direct assay. Source: UniProtKB transcription Inferred from electronic annotation. Source: UniProtKB-KW transforming growth factor beta receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	ATP binding Ref.1 Inferred from direct assay. Source: UniProtKB MAP kinase activity Ref.1 Inferred from direct assay. Source: UniProtKB SH2 domain binding Ref.6 Inferred from physical interaction. Source: UniProtKB magnesium ion binding Ref.1 Inferred from direct assay. Source: UniProtKB transcription factor binding Inferred from sequence or structural similarity. Source: UniProtKB ubiquitin protein ligase binding Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Hipk2	Q9QZR5	1	EBI-366894,EBI-366905
Myb	P06876	1	EBI-366894,EBI-366934

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 527	527	Serine/threonine protein kinase NLK		PRO_0000186337
Regions
	Domain	138 – 427	290	Protein kinase
	Nucleotide binding	144 – 152	9	ATP By similarity
	Motif	303 – 305	3	TXY
	Compositional bias	22 – 25	4	Poly-Ala
	Compositional bias	27 – 34	8	Poly-His
	Compositional bias	42 – 48	7	Poly-His
	Compositional bias	71 – 83	13	Poly-Ala
	Compositional bias	106 – 111	6	Poly-Ala
	Compositional bias	115 – 119	5	Poly-Ala
Sites
	Active site	264	1	Proton acceptor By similarity
	Binding site	167	1	ATP
Amino acid modifications
	Modified residue	298	1	Phosphothreonine Ref.9
	Modified residue	303	1	Phosphothreonine By similarity
	Modified residue	305	1	Phosphotyrosine By similarity
Experimental info
	Mutagenesis	167	1	K → M: Loss of activity, autophosphorylation and failed to induce MYB degradation. Ref.1 Ref.7
	Mutagenesis	298	1	T → D or E: Loss of autophosphorylation. Ref.1 Ref.7
	Mutagenesis	298	1	T → V: Loss of autophosphorylation and failed to induce MYB degradation. Ref.1 Ref.7
	Sequence conflict	69	1	S → P in AAC24499. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	O54949-1 [UniParc]. Last modified November 3, 2009. Version 2. Checksum: CE6D5DCCB9133989	FASTA	527	58,313
	10 20 30 40 50 60 MSLCGTRANA KMMAAYNGGT SAAAAGHHHH HHHHLPHLPP PHLHHHHHPQ HHLHPGSAAA 70 80 90 100 110 120 VHPVQQHTSS AAAAAAAAAA AAAMLNPGQQ QPYFPSPAPG QAPGPAAAAP AQVQAAAAAT 130 140 150 160 170 180 VKAHHHQHSH HPQQQLDIEP DRPIGYGAFG VVWSVTDPRD GKRVALKKMP NVFQNLVSCK 190 200 210 220 230 240 RVFRELKMLC FFKHDNVLSA LDILQPPHID YFEEIYVVTE LMQSDLHKII VSPQPLSSDH 250 260 270 280 290 300 VKVFLYQILR GLKYLHSAGI LHRDIKPGNL LVNSNCVLKI CDFGLARVEE LDESRHMTQE 310 320 330 340 350 360 VVTQYYRAPE ILMGSRHYSN AIDIWSVGCI FAELLGRRIL FQAQSPIQQL DLITDLLGTP 370 380 390 400 410 420 SLEAMRTACE GAKAHILRGP HKQPSLPVLY TLSSQATHEA VHLLCRMLVF DPSKRISAKD 430 440 450 460 470 480 ALAHPYLDEG RLRYHTCMCK CCFSTSTGRV YTSDFEPVTN PKFDDTFEKN LSSVRQVKEI 490 500 510 520 IHQFILEQQK GNRVPLCINP QSAAFKSFIS STVAQPSEMP PSPLVWE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Nlk is a murine protein kinase related to Erk/MAP kinases and localized in the nucleus." Brott B.K., Pinsky B.A., Erikson R.L. Proc. Natl. Acad. Sci. U.S.A. 95:963-968(1998) [PubMed: 9448268] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, ENZYME REGULATION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AUTOPHOSPHORYLATION, MUTAGENESIS OF LYS-167 AND THR-298. Strain: BALB/c. Tissue: Brain.
[2]	"Lineage-specific biology revealed by a finished genome assembly of the mouse." Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P. PLoS Biol. 7:E1000112-E1000112(2009) [PubMed: 19468303] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: C57BL/6.
[3]	"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]. Strain: C57BL/6 and FVB/N. Tissue: Brain and Kidney.
[4]	"Abnormal bone marrow stroma in mice deficient for nemo-like kinase, Nlk." Kortenjann M., Nehls M., Smith A.J., Carsetti R., Schuler J., Kohler G., Boehm T. Eur. J. Immunol. 31:3580-3587(2001) [PubMed: 11745377] [Abstract] Cited for: FUNCTION.
[5]	"Nemo-like kinase suppresses a wide range of transcription factors, including nuclear factor-kappaB." Yasuda J., Yokoo H., Yamada T., Kitabayashi I., Sekiya T., Ichikawa H. Cancer Sci. 95:52-57(2004) [PubMed: 14720327] [Abstract] Cited for: FUNCTION.
[6]	"Role of the TAK1-NLK-STAT3 pathway in TGF-beta-mediated mesoderm induction." Ohkawara B., Shirakabe K., Hyodo-Miura J., Matsuo R., Ueno N., Matsumoto K., Shibuya H. Genes Dev. 18:381-386(2004) [PubMed: 15004007] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH STAT3.
[7]	"Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK." Kanei-Ishii C., Ninomiya-Tsuji J., Tanikawa J., Nomura T., Ishitani T., Kishida S., Kokura K., Kurahashi T., Ichikawa-Iwata E., Kim Y., Matsumoto K., Ishii S. Genes Dev. 18:816-829(2004) [PubMed: 15082531] [Abstract] Cited for: FUNCTION, INTERACTION WITH MYB AND HIPK2, MUTAGENESIS OF LYS-167 AND THR-298.
[8]	"Nemo-like kinase-myocyte enhancer factor 2A signaling regulates anterior formation in Xenopus development." Satoh K., Ohnishi J., Sato A., Takeyama M., Iemura S., Natsume T., Shibuya H. Mol. Cell. Biol. 27:7623-7630(2007) [PubMed: 17785444] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH MEF2A.
[9]	"Qualitative and quantitative analyses of protein phosphorylation in naive and stimulated mouse synaptosomal preparations." Munton R.P., Tweedie-Cullen R., Livingstone-Zatchej M., Weinandy F., Waidelich M., Longo D., Gehrig P., Potthast F., Rutishauser D., Gerrits B., Panse C., Schlapbach R., Mansuy I.M. Mol. Cell. Proteomics 6:283-293(2007) [PubMed: 17114649] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-298, MASS SPECTROMETRY. Tissue: Brain cortex.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	AF036332 mRNA. Translation: AAC24499.1. Different initiation. AL591177, AL591376 Genomic DNA. Translation: CAI25549.2. AL591376, AL591177 Genomic DNA. Translation: CAI25603.2. BC057667 mRNA. Translation: AAH57667.2. BC058652 mRNA. Translation: AAH58652.2.
IPI	IPI00556914.
RefSeq	NP_032728.3. XP_001472539.1.
UniGene	Mm.9001
3D structure databases
ModBase	Search...
Protein-protein interaction databases
IntAct	O54949. 2 interactions.
STRING	O54949.
PTM databases
PhosphoSite	O54949.
Proteomic databases
PRIDE	O54949.
Genome annotation databases
Ensembl	ENSMUST00000017520; ENSMUSP00000017520; ENSMUSG00000017376; Mus musculus. [Genome view]
GeneID	100044468. 18099.
KEGG	mmu:100044468. mmu:18099.
Organism-specific databases
CTD	18099.
MGI	MGI:1201387. Nlk.
Phylogenomic databases
HOGENOM	O54949.
HOVERGEN	O54949.
Enzyme and pathway databases
BRENDA	2.7.11.24. 244.
Gene expression databases
ArrayExpress	O54949.
Bgee	O54949.
CleanEx	MM_NLK.
Genevestigator	O54949.
GermOnline	ENSMUSG00000017376. Mus musculus.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR003527. MAP_kinase_CS. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR017442. Se/Thr_prot_kinase-like_dom. IPR008271. Ser/Thr_prot_kinase_AS. IPR002290. Ser/Thr_prot_kinase_dom. [Graphical view]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
PROSITE	PS01351. MAPK. 1 hit. PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
SOURCE	Search...

Entry information

Entry name

NLK_MOUSE

Accession

Primary (citable) accession number: O54949
Secondary accession number(s): Q5SYE6, Q6PF98

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 19, 2004
Last sequence update:	November 3, 2009
Last modified:	November 24, 2009
This is version 82 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)