Reviewed, UniProtKB/Swiss-Prot Q80Z64 (NANOG_MOUSE)

Names and origin

Protein names

Recommended name:
    Homeobox protein NANOG
Alternative name(s):
    Homeobox transcription factor Nanog
    Early embryo specific expression NK-type homeobox protein
    ES cell-associated protein 4

Gene names

Name:	Nanog
Synonyms:	Ecat4, Enk

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	305 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Transcription regulator involved in inner cell mass and embryonic stem (ES) cells proliferation and self-renewal. Imposes pluripotency on ES cells and prevents their differentiation towards extraembryonic endoderm and trophectoderm lineages. Blocks bone morphogenetic protein-induced mesoderm differentiation of ES cells by physically interacting with SMAD1 and interfering with the recruitment of coactivators to the active SMAD transcriptional complexes. Acts as a transcriptional activator or repressor. Binds optimally to the DNA consensus sequence 5'-TAAT[GT][GT]-3' or 5'-[CG][GA][CG]C[GC]ATTAN[GC]-3'. When overexpressed, promotes cells to enter into S phase and proliferation By similarity. Ref.1 Ref.2 Ref.6 Ref.8 Ref.13 Ref.14 Ref.15
Subunit structure	Interacts with SMAD1 and SALL4. Ref.15 Ref.12 Ref.16
Subcellular location	Nucleus Ref.9.
Tissue specificity	Not expressed in oocytes and spermatogonia (at protein level). Not expressed in many somatic organs, ovary, testis, fibroblast and hematopoietic cell lines. Ref.1 Ref.2 Ref.4 Ref.7
Developmental stage	Expressed in the central portion of the morula, the inner cell mass (ICM) of the blastocyst, in embryonic stem (ES) and embryonic germ (EG) cells, in the epiblast between 6.5 and 7.5 dpc, in primordial germ cells (PGCs) between 7.75 and 12.5 dpc (at protein level). The expression in PGCs decreases in female germ cells that entered meiosis at 13.5 dpc and in male germ cells that entered mitotic arrest at 14.5 dpc (at protein level). Not expressed in unfertilized eggs or 2- or 8-cell-stage embryos (at protein level). Expressed in the central portion of the morula, the inner cell mass (ICM) of the blastocyst, in ES and EG cells, in the epiblast at 6 dpc and in PGCs of genital ridges between 11.5 and 12.5 dpc. Expression decreases with ES differentiation. Ref.1 Ref.2 Ref.9 Ref.4 Ref.7 Ref.3
Induction	By the transcription factor POU5F1 in ES cells that acts as a direct biphasic regulator: a steady-state concentration of POU5F1 up-regulated its expression, while an elevated concentration of POU5F1 down-regulated its expression. Up-regulated by the transcription factor FOXD3. Up-regulated in ES cells by transcription factors T (Brachyury) and STAT3. Down-regulated by p53 in response to DNA damage induced by ultraviolet light (UV) or doxorubicin. Down-regulated upon ES differentiation. Ref.14 Ref.15 Ref.10 Ref.11
Miscellaneous	Knockout mice resulted in loss of pluripotency in both ICM and ES cells and differentiated into extraembryonic (parietal and visceral) endoderm lineage. 'Nanog' is derived from 'Tir nan Og' the mythologic Celtic land of the ever young.
Sequence similarities	Belongs to the Nanog homeobox family. Contains 1 homeobox DNA-binding domain.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing
Domain	Homeobox Repeat
Ligand	DNA-binding
Molecular function	Activator Developmental protein Repressor
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	embryonic pattern specification Ref.4 Inferred from expression pattern. Source: HGNC gonad development Ref.4 Inferred from expression pattern. Source: HGNC mesodermal cell fate commitment Ref.15 Inferred from genetic interaction. Source: MGI negative regulation of BMP signaling pathway Ref.15 Inferred from direct assay. Source: MGI negative regulation of endodermal cell fate specification Traceable author statement. Source: HGNC negative regulation of transcription from RNA polymerase II promoter Ref.15 Inferred from genetic interaction. Source: MGI positive regulation of cell proliferation Inferred from direct assay. Source: MGI positive regulation of mitotic cell cycle Inferred from direct assay. Source: MGI response to retinoic acid Inferred from direct assay. Source: MGI stem cell division Ref.2 Inferred from direct assay. Source: MGI stem cell maintenance Ref.1 Ref.15 Inferred from direct assay. Source: MGI transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	nucleus Ref.9 Inferred from direct assay. Source: MGI
Molecular function	protein binding Inferred from physical interaction. Source: IntAct sequence-specific DNA binding Inferred from direct assay. Source: MGI transcription factor activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Nr0b1	Q61066	4	EBI-2312517,EBI-2312665
Pou5f1	P20263	3	EBI-2312517,EBI-1606219
Rif1	Q6PR54	2	EBI-2312517,EBI-2312621
Slc8a1	P70414	3	EBI-2312517,EBI-2312694
Zfp281	Q4FK52	3	EBI-2312517,EBI-2312719

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q80Z64-1)

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.

Isoform 2 (identifier: Q80Z64-2)

Also known as: Nanog1a; Nanog1b;

The sequence of this isoform differs from the canonical sequence as follows:
     1-25: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 305

305

Homeobox protein NANOG

PRO_0000261419

Regions

Repeat

198 – 202

5

1

Repeat

203 – 207

5

2

Repeat

208 – 212

5

3

Repeat

213 – 217

5

4

Repeat

218 – 222

5

5

Repeat

223 – 227

5

6

Repeat

228 – 232

5

7

Repeat

233 – 237

5

8

Repeat

238 – 242

5

9

Repeat

243 – 247

5

10

DNA binding

96 – 155

60

Homeobox Ref.1 Ref.8 Ref.12

Region

96 – 155

60

Sufficient for interaction with SALL4

Region

198 – 247

50

10 X repeats starting with a Trp in each unit

Region

198 – 247

50

Sufficient for transactivation activity

Region

248 – 305

58

Sufficient for strong transactivation activity

Compositional bias

198 – 243

46

Trp-rich

Natural variations

Alternative sequence

1 – 25

25

Missing in isoform 2.

VSP_021689

Experimental info

Mutagenesis

112

1

K → E: Increases affinity for DNA and protein stability; when associated with R-147. Ref.16

Mutagenesis

126

1

M → R: Increases affinity for DNA; when associated with E-137. Ref.16

Mutagenesis

137

1

Y → E: Increases affinity for DNA; when associated with R-126. Ref.16

Mutagenesis

138

1

K → E: Reduced affinity for DNA. Ref.16

Mutagenesis

142

1

T → I: Slightly reduced affinity for DNA. Ref.16

Mutagenesis

146

1

N → E: Strongly reduced affinity for DNA. Ref.16

Mutagenesis

147

1

Q → R: Increases affinity for DNA and protein stability; when associated with E-112. Ref.16

Sequence conflict

149

1

M → V in BAC76998. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

305

Helix Strand Turn

Details...

Helix

105 – 117

13

Helix

123 – 133

11

Helix

137 – 149

13

Helix

152 – 154

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified June 1, 2003. Version 1. Checksum: 4EF96408B767C79F	FASTA	305	34,240
	10 20 30 40 50 60 MSVGLPGPHS LPSSEEASNS GNASSMPAVF HPENYSCLQG SATEMLCTEA ASPRPSSEDL 70 80 90 100 110 120 PLQGSPDSST SPKQKLSSPE ADKGPEEEEN KVLARKQKMR TVFSQAQLCA LKDRFQKQKY 130 140 150 160 170 180 LSLQQMQELS SILNLSYKQV KTWFQNQRMK CKRWQKNQWL KTSNGLIQKG SAPVEYPSIH 190 200 210 220 230 240 CSYPQGYLVN ASGSLSMWGS QTWTNPTWSS QTWTNPTWNN QTWTNPTWSS QAWTAQSWNG 250 260 270 280 290 300 QPWNAAPLHN FGEDFLQPYV QLQQNFSASD LEVNLEATRE SHAHFSTPQA LELFLNYSVT PPGEI
	Isoform 2 (Nanog1a) (Nanog1b). Checksum: 090B8AC6C26A37C6	FASTA	280	31,859
	10 20 30 40 50 60 MPAVFHPENY SCLQGSATEM LCTEAASPRP SSEDLPLQGS PDSSTSPKQK LSSPEADKGP 70 80 90 100 110 120 EEEENKVLAR KQKMRTVFSQ AQLCALKDRF QKQKYLSLQQ MQELSSILNL SYKQVKTWFQ 130 140 150 160 170 180 NQRMKCKRWQ KNQWLKTSNG LIQKGSAPVE YPSIHCSYPQ GYLVNASGSL SMWGSQTWTN 190 200 210 220 230 240 PTWSSQTWTN PTWNNQTWTN PTWSSQAWTA QSWNGQPWNA APLHNFGEDF LQPYVQLQQN 250 260 270 280 FSASDLEVNL EATRESHAHF STPQALELFL NYSVTPPGEI

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells." Mitsui K., Tokuzawa Y., Itoh H., Segawa K., Murakami M., Takahashi K., Maruyama M., Maeda M., Yamanaka S. Cell 113:631-642(2003) [PubMed: 12787504] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, DNA-BINDING, DEVELOPMENTAL STAGE, TISSUE SPECIFICITY.
[2]	"Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells." Chambers I., Colby D., Robertson M., Nichols J., Lee S., Tweedie S., Smith A. Cell 113:643-655(2003) [PubMed: 12787505] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, DEVELOPMENTAL STAGE, TISSUE SPECIFICITY. Strain: 129/Ola. Tissue: Embryonic stem cell.
[3]	"A novel NK-type homeobox gene, ENK (early embryo specific NK), preferentially expressed in embryonic stem cells." Wang S.-H., Tsai M.-S., Chiang M.-F., Li H. Gene Expr. Patterns 3:99-103(2003) [PubMed: 12609610] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), DEVELOPMENTAL STAGE. Strain: FVB. Tissue: Embryonic stem cell.
[4]	"Identification, cloning and expression analysis of the pluripotency promoting Nanog genes in mouse and human." Hart A.H., Hartley L., Ibrahim M., Robb L. Dev. Dyn. 230:187-198(2004) [PubMed: 15108323] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), DEVELOPMENTAL STAGE, TISSUE SPECIFICITY. Strain: C57BL/6.
[5]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed: 16141072] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Strain: C57BL/6J. Tissue: Embryonic stem cell.
[6]	"Identification of two distinct transactivation domains in the pluripotency sustaining factor nanog." Pan G.J., Pei D.Q. Cell Res. 13:499-502(2003) [PubMed: 14728807] [Abstract] Cited for: FUNCTION.
[7]	"Nanog expression in mouse germ cell development." Yamaguchi S., Kimura H., Tada M., Nakatsuji N., Tada T. Gene Expr. Patterns 5:639-646(2005) [PubMed: 15939376] [Abstract] Cited for: DEVELOPMENTAL STAGE, TISSUE SPECIFICITY.
[8]	"The stem cell pluripotency factor NANOG activates transcription with two unusually potent subdomains at its C terminus." Pan G., Pei D. J. Biol. Chem. 280:1401-1407(2005) [PubMed: 15502159] [Abstract] Cited for: FUNCTION, DNA-BINDING.
[9]	"Pluripotential competence of cells associated with Nanog activity." Hatano S.Y., Tada M., Kimura H., Yamaguchi S., Kono T., Nakano T., Suemori H., Nakatsuji N., Tada T. Mech. Dev. 122:67-79(2005) [PubMed: 15582778] [Abstract] Cited for: SUBCELLULAR LOCATION, DEVELOPMENTAL STAGE.
[10]	"p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression." Lin T., Chao C., Saito S., Mazur S.J., Murphy M.E., Appella E., Xu Y. Nat. Cell Biol. 7:165-171(2005) [PubMed: 15619621] [Abstract] Cited for: INDUCTION.
[11]	"A negative feedback loop of transcription factors that controls stem cell pluripotency and self-renewal." Pan G., Li J., Zhou Y., Zheng H., Pei D. FASEB J. 20:1730-1732(2006) [PubMed: 16790525] [Abstract] Cited for: INDUCTION.
[12]	"Sall4 interacts with Nanog and co-occupies Nanog genomic sites in embryonic stem cells." Wu Q., Chen X., Zhang J., Loh Y.-H., Low T.-Y., Zhang W., Zhang W., Sze S.-K., Lim B., Ng H.-H. J. Biol. Chem. 281:24090-24094(2006) [PubMed: 16840789] [Abstract] Cited for: INTERACTION WITH SALL4, DNA-BINDING.
[13]	"Nanog promotes transfer of pluripotency after cell fusion." Silva J., Chambers I., Pollard S., Smith A. Nature 441:997-1001(2006) [PubMed: 16791199] [Abstract] Cited for: FUNCTION.
[14]	"The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells." Loh Y.-H., Wu Q., Chew J.-L., Vega V.B., Zhang W., Chen X., Bourque G., George J., Leong B., Liu J., Wong K.-Y., Sung K.W., Lee C.W., Zhao X.-D., Chiu K.-P., Lipovich L., Kuznetsov V.A., Robson P. , Stanton L.W., Wei C.-L., Ruan Y., Lim B., Ng H.-H. Nat. Genet. 38:431-440(2006) [PubMed: 16518401] [Abstract] Cited for: FUNCTION, INDUCTION.
[15]	"Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells." Suzuki A., Raya A., Kawakami Y., Morita M., Matsui T., Nakashima K., Gage F.H., Rodriguez-Esteban C., Izpisua Belmonte J.C. Proc. Natl. Acad. Sci. U.S.A. 103:10294-10299(2006) [PubMed: 16801560] [Abstract] Cited for: FUNCTION, INTERACTION WITH SMAD1, INDUCTION.
[16]	"Crystal structure and DNA binding of the homeodomain of the stem cell transcription factor Nanog." Jauch R., Ng C.K.L., Saikatendu K.S., Stevens R.C., Kolatkar P.R. J. Mol. Biol. 376:758-770(2008) [PubMed: 18177668] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 96-155, INTERACTION WITH DNA, PARTIAL PROTEIN SEQUENCE, MUTAGENESIS OF LYS-112; MET-126; TYR-137; LYS-138; THR-142; ASN-146 AND GLN-147.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AB093574 mRNA. Translation: BAC76998.1.
AY278951 mRNA. Translation: AAP92157.1.
AF507043 mRNA. Translation: AAO67362.1.
AY455282 mRNA. Translation: AAS57554.1.
AY455285 mRNA. Translation: AAS57556.1.
AK010332 mRNA. Translation: BAE43219.1.

IPI

IPI00109731.
IPI00807949.

RefSeq

NP_082292.1.

UniGene

Mm.478080
Mm.6047

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2VI6	X-ray	2.60	A/B/C/D/E/F/G/H	96-155	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29925N.
DIP-29932N.

IntAct

Q80Z64. 17 interactions.

STRING

Q80Z64.

Proteomic databases

PRIDE

Q80Z64.

Genome annotation databases

Ensembl

ENSMUST00000012540; ENSMUSP00000012540; ENSMUSG00000012396; Mus musculus. [Genome view]

GeneID

71950.

KEGG

mmu:71950.

UCSC

uc009dpo.1. mouse.

Organism-specific databases

CTD

71950.

MGI

MGI:1919200. Nanog.

Phylogenomic databases

HOGENOM

HBG126619.

HOVERGEN

Q80Z64.

InParanoid

Q80Z64.

OMA

HDSSTSP.

PhylomeDB

Q80Z64.

Gene expression databases

ArrayExpress

Q80Z64.

Bgee

Q80Z64.

Genevestigator

Q80Z64.

GermOnline

ENSMUSG00000012396. Mus musculus.

Family and domain databases

InterPro

IPR001356. Homeobox.
IPR017970. Homeobox_CS.
IPR009057. Homeodomain-like.
IPR012287. Homeodomain-rel.
[Graphical view]

Gene3D

G3DSA:1.10.10.60. Homeodomain-rel. 1 hit.

Pfam

PF00046. Homeobox. 1 hit.
[Graphical view]

SMART

SM00389. HOX. 1 hit.
[Graphical view]

PROSITE

PS00027. HOMEOBOX_1. 1 hit.
PS50071. HOMEOBOX_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

335028.

SOURCE

Search...

Entry information

Entry name

NANOG_MOUSE

Accession

Primary (citable) accession number: Q80Z64
Secondary accession number(s): Q6SMR1, Q7TN85

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 28, 2006
Last sequence update:	June 1, 2003
Last modified:	January 19, 2010
This is version 60 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)