Reviewed, UniProtKB/Swiss-Prot O15169 (AXN1_HUMAN)

Names and origin

Protein names

Recommended name:
    Axin-1
Alternative name(s):
    Axis inhibition protein 1
      Short name=hAxin

Gene names

Name:	AXIN1
Synonyms:	AXIN

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

Protein attributes

Sequence length	862 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Controls dorsoventral patterning via two opposing effects; down-regulates beta-catenin to inhibit the Wnt signaling pathway and ventralize embryos, but also dorsalizes embryos by activating a Wnt-independent JNK signaling pathway. In Wnt signaling, probably facilitates the phosphorylation of beta-catenin and APC by GSK3B. Likely to function as a tumor suppressor. Facilitates the phosphorylation of TP53 by HIPK2 upon ultraviolet irradiation. Wild-type axin 1 can induce apoptosis in hepatocellular and colorectal cancer cells. Enhances TGF-beta signaling by recruiting the RNF111 E3 ubiquitin ligase and promoting the degradation of inhibitory SMAD7. Ref.7
Subunit structure	Homodimer By similarity. Interacts with TP53 and HIPK2. Probably part of a complex consisting of TP53, HIPK2 and AXIN1. Interacts with glycogen synthase kinase-3 beta (GSK3B) and beta-catenin. The interaction between axin and beta-catenin occurs via the armadillo repeats contained in beta-catenin. Ternary complex. Also binds to plakoglobin (gamma-catenin), APC, DVL and PP2A. Interacts with SMAD6, SMAD7 and RNF111. Interacts with DIXDC1; prevents interaction with MAP3K1. Interacts with MAP3K4, MDFI and MDFIC. Interacts with ANKRD6. Interacts with AIDA.
Subcellular location	Cytoplasm. Ref.7
Tissue specificity	Ubiquitously expressed.
Post-translational modification	Probably phosphorylated by GSK3B and dephosphorylated by PP2A.
Involvement in disease	Defects in AXIN1 are involved in hepatocellular carcinoma (HCC) [MIM:114550]. Ref.9 Ref.11 Hypermethylation of the AXIN1 promoter may be associated with caudal duplication anomaly [MIM:607864]. Caudal duplication anomaly is characterized by the occurrence of duplications of different organs in the caudal region. Ref.9
Sequence similarities	Contains 1 DIX domain. Contains 1 RGS domain.

Ontologies

Keywords
Biological process	Apoptosis Wnt signaling pathway
Cellular component	Cytoplasm
Coding sequence diversity	Alternative splicing
Disease	Disease mutation Tumor suppressor
Molecular function	Developmental protein
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	Wnt receptor signaling pathway through beta-catenin Inferred by curator. Source: UniProtKB apoptosis Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of Wnt receptor signaling pathway Inferred from direct assay. Source: UniProtKB oocyte axis specification Ref.1 Traceable author statement. Source: UniProtKB positive regulation of JNK cascade Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of peptidyl-serine phosphorylation Inferred from direct assay. Source: UniProtKB positive regulation of peptidyl-threonine phosphorylation Inferred from direct assay. Source: UniProtKB positive regulation of protein ubiquitination Inferred from direct assay. Source: UniProtKB
Cellular component	beta-catenin destruction complex Inferred from direct assay. Source: UniProtKB cytoplasmic vesicle Inferred from sequence or structural similarity. Source: UniProtKB cytosol Inferred from Experiment. Source: Reactome lateral plasma membrane Inferred from direct assay. Source: MGI nucleus Inferred from direct assay. Source: MGI
Molecular function	I-SMAD binding Inferred from physical interaction. Source: UniProtKB armadillo repeat domain binding Inferred from sequence or structural similarity. Source: UniProtKB beta-catenin binding Inferred from direct assay. Source: UniProtKB protein homodimerization activity Inferred from sequence or structural similarity. Source: UniProtKB signal transducer activity Ref.1 Non-traceable author statement. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ANP32A	P39687	1	EBI-710484,EBI-359234
CRMP1	Q14194	1	EBI-710484,EBI-473101
Ctnnb1	Q02248	2	EBI-710484,EBI-397872	From a different organism.
GSK3B	P49841	1	EBI-710484,EBI-373586
SMYD2	Q9NRG4	1	EBI-710484,EBI-1055671

Alternative products

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

Isoform 1 (identifier: O15169-1)

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: O15169-2)

The sequence of this isoform differs from the canonical sequence as follows:
     730-765: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 862

862

Axin-1

PRO_0000220888

Regions

Domain

88 – 211

124

RGS

Domain

780 – 862

83

DIX

Region

209 – 338

130

Interaction with TP53 By similarity

Region

348 – 433

86

Interaction with GSK3B By similarity

Region

434 – 502

69

Interaction with beta-catenin By similarity

Region

507 – 757

251

Interaction with RNF111

Region

677 – 752

76

Interaction with HIPK2 By similarity

Amino acid modifications

Modified residue

493

1

Phosphoserine By similarity

Natural variations

Alternative sequence

730 – 765

36

Missing in isoform 2.

VSP_019398

Natural variant

106

1

L → R in HCC. Ref.11

VAR_015589

Natural variant

345

1

P → L in HCC. Ref.11

VAR_015590

Natural variant

425

1

G → S in HCC. Ref.11

VAR_015591

Natural variant

650

1

G → S in HCC and in hepatoblastoma. Ref.11

VAR_015592

Natural variant

841

1

R → Q in hepatoblastoma. Ref.11

VAR_015593

Experimental info

Sequence conflict

360

1

V → A in AAC51624. Ref.1

Sequence conflict

451 – 455

5

CVDMG → LCWTWA in AAC51624. Ref.1

Sequence conflict

482

1

P → T in AAC51624. Ref.1

Secondary structure

1

.

.

.

.

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862

Helix Strand Turn

Details...

Helix

81 – 87

7

Helix

89 – 92

4

Helix

96 – 107

12

Turn

108 – 110

3

Helix

112 – 126

15

Helix

134 – 148

15

Helix

155 – 159

5

Helix

162 – 174

13

Turn

179 – 182

4

Helix

183 – 195

13

Helix

197 – 201

5

Helix

205 – 208

4

Turn

209 – 212

4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified May 10, 2002. Version 2. Checksum: 10779173F5092F3F	FASTA	862	95,635
	10 20 30 40 50 60 MNIQEQGFPL DLGASFTEDA PRPPVPGEEG ELVSTDPRPA SYSFCSGKGV GIKGETSTAT 70 80 90 100 110 120 PRRSDLDLGY EPEGSASPTP PYLKWAESLH SLLDDQDGIS LFRTFLKQEG CADLLDFWFA 130 140 150 160 170 180 CTGFRKLEPC DSNEEKRLKL ARAIYRKYIL DNNGIVSRQT KPATKSFIKG CIMKQLIDPA 190 200 210 220 230 240 MFDQAQTEIQ ATMEENTYPS FLKSDIYLEY TRTGSESPKV CSDQSSGSGT GKGISGYLPT 250 260 270 280 290 300 LNEDEEWKCD QDMDEDDGRD AAPPGRLPQK LLLETAAPRV SSSRRYSEGR EFRYGSWREP 310 320 330 340 350 360 VNPYYVNAGY ALAPATSAND SEQQSLSSDA DTLSLTDSSV DGIPPYRIRK QHRREMQESV 370 380 390 400 410 420 QVNGRVPLPH IPRTYRVPKE VRVEPQKFAE ELIHRLEAVQ RTREAEEKLE ERLKRVRMEE 430 440 450 460 470 480 EGEDGDPSSG PPGPCHKLPP APAWHHFPPR CVDMGCAGLR DAHEENPESI LDEHVQRVLR 490 500 510 520 530 540 TPGRQSPGPG HRSPDSGHVA KMPVALGGAA SGHGKHVPKS GAKLDAAGLH HHRHVHHHVH 550 560 570 580 590 600 HSTARPKEQV EAEATRRAQS SFAWGLEPHS HGARSRGYSE SVGAAPNASD GLAHSGKVGV 610 620 630 640 650 660 ACKRNAKKAE SGKSASTEVP GASEDAEKNQ KIMQWIIEGE KEISRHRRTG HGSSGTRKPQ 670 680 690 700 710 720 PHENSRPLSL EHPWAGPQLR TSVQPSHLFI QDPTMPPHPA PNPLTQLEEA RRRLEEEEKR 730 740 750 760 770 780 ASRAPSKQRY VQEVMRRGRA CVRPACAPVL HVVPAVSDME LSETETRSQR KVGGGSAQPC 790 800 810 820 830 840 DSIVVAYYFC GEPIPYRTLV RGRAVTLGQF KELLTKKGSY RYYFKKVSDE FDCGVVFEEV 850 860 REDEAVLPVF EEKIIGKVEK VD
	Isoform 2. Checksum: 4AA4187D70A5863D	FASTA	826	91,653
	10 20 30 40 50 60 MNIQEQGFPL DLGASFTEDA PRPPVPGEEG ELVSTDPRPA SYSFCSGKGV GIKGETSTAT 70 80 90 100 110 120 PRRSDLDLGY EPEGSASPTP PYLKWAESLH SLLDDQDGIS LFRTFLKQEG CADLLDFWFA 130 140 150 160 170 180 CTGFRKLEPC DSNEEKRLKL ARAIYRKYIL DNNGIVSRQT KPATKSFIKG CIMKQLIDPA 190 200 210 220 230 240 MFDQAQTEIQ ATMEENTYPS FLKSDIYLEY TRTGSESPKV CSDQSSGSGT GKGISGYLPT 250 260 270 280 290 300 LNEDEEWKCD QDMDEDDGRD AAPPGRLPQK LLLETAAPRV SSSRRYSEGR EFRYGSWREP 310 320 330 340 350 360 VNPYYVNAGY ALAPATSAND SEQQSLSSDA DTLSLTDSSV DGIPPYRIRK QHRREMQESV 370 380 390 400 410 420 QVNGRVPLPH IPRTYRVPKE VRVEPQKFAE ELIHRLEAVQ RTREAEEKLE ERLKRVRMEE 430 440 450 460 470 480 EGEDGDPSSG PPGPCHKLPP APAWHHFPPR CVDMGCAGLR DAHEENPESI LDEHVQRVLR 490 500 510 520 530 540 TPGRQSPGPG HRSPDSGHVA KMPVALGGAA SGHGKHVPKS GAKLDAAGLH HHRHVHHHVH 550 560 570 580 590 600 HSTARPKEQV EAEATRRAQS SFAWGLEPHS HGARSRGYSE SVGAAPNASD GLAHSGKVGV 610 620 630 640 650 660 ACKRNAKKAE SGKSASTEVP GASEDAEKNQ KIMQWIIEGE KEISRHRRTG HGSSGTRKPQ 670 680 690 700 710 720 PHENSRPLSL EHPWAGPQLR TSVQPSHLFI QDPTMPPHPA PNPLTQLEEA RRRLEEEEKR 730 740 750 760 770 780 ASRAPSKQRT RSQRKVGGGS AQPCDSIVVA YYFCGEPIPY RTLVRGRAVT LGQFKELLTK 790 800 810 820 KGSYRYYFKK VSDEFDCGVV FEEVREDEAV LPVFEEKIIG KVEKVD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation." Zeng L., Fagotto F., Zhang T., Hsu W., Vasicek T.J., Perry W.L. III, Lee J.J., Tilghman S.M., Gumbiner B.M., Costantini F. Cell 90:181-192(1997) [PubMed: 9230313] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"Sequence, structure and pathology of the fully annotated terminal 2 Mb of the short arm of human chromosome 16." Daniels R.J., Peden J.F., Lloyd C., Horsley S.W., Clark K., Tufarelli C., Kearney L., Buckle V.J., Doggett N.A., Flint J., Higgs D.R. Hum. Mol. Genet. 10:339-352(2001) [PubMed: 11157797] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"The sequence and analysis of duplication-rich human chromosome 16." Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J. , Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M., Rubin E.M., Pennacchio L.A. Nature 432:988-994(2004) [PubMed: 15616553] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[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] (ISOFORM 2), NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 471-862 (ISOFORM 1). Tissue: Lymphoma and Renal cell carcinoma.
[5]	"I-mfa domain proteins interact with Axin and affect its regulation of the Wnt and c-Jun N-terminal kinase signaling pathways." Kusano S., Raab-Traub N. Mol. Cell. Biol. 22:6393-6405(2002) [PubMed: 12192039] [Abstract] Cited for: INTERACTION WITH MDFI AND MDFIC.
[6]	"The DIX domain protein coiled-coil-DIX1 inhibits c-Jun N-terminal kinase activation by Axin and dishevelled through distinct mechanisms." Wong C.K., Luo W., Deng Y., Zou H., Ye Z., Lin S.-C. J. Biol. Chem. 279:39366-39373(2004) [PubMed: 15262978] [Abstract] Cited for: INTERACTION WITH DIXDC1; MAP3K1 AND MAP3K4.
[7]	"Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia." Liu W., Rui H., Wang J., Lin S., He Y., Chen M., Li Q., Ye Z., Zhang S., Chan S.C., Chen Y.-G., Han J., Lin S.-C. EMBO J. 25:1646-1658(2006) [PubMed: 16601693] [Abstract] Cited for: INTERACTION WITH SMAD6; SMAD7 AND RNF111, FUNCTION, SUBCELLULAR LOCATION.
[8]	"Structural basis of the axin-adenomatous polyposis coli interaction." Spink K.E., Polakis P., Weis W.I. EMBO J. 19:2270-2279(2000) [PubMed: 10811618] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.57 ANGSTROMS) OF 74-220 IN COMPLEX WITH APC.
[9]	"AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1." Satoh S., Daigo Y., Furukawa Y., Kato T., Miwa N., Nishiwaki T., Kawasoe T., Ishiguro H., Fujita M., Tokino T., Sasaki Y., Imaoka S., Murata M., Shimano T., Yamaoka Y., Nakamura Y. Nat. Genet. 24:245-250(2000) [PubMed: 10700176] [Abstract] Cited for: DISEASE.
[10]	"Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complex." Dajani R., Fraser E., Roe S.M., Yeo M., Good V.M., Thompson V., Dale T.C., Pearl L.H. EMBO J. 22:494-501(2003) [PubMed: 12554650] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 383-400 IN COMPLEX WITH GSK3B.
[11]	"Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas." Taniguchi K., Roberts L.R., Aderca I.N., Dong X., Qian C., Murphy L.M., Nagorney D.M., Burgart L.J., Roche P.C., Smith D.I., Ross J.A., Liu W. Oncogene 21:4863-4871(2002) [PubMed: 12101426] [Abstract] Cited for: VARIANTS HCC ARG-106; LEU-345; SER-425 AND SER-650, VARIANT HEPATOBLASTOMA GLN-841.
[12]	"Increased DNA methylation at the AXIN1 gene in a monozygotic twin from a pair discordant for a caudal duplication anomaly." Oates N.A., van Vliet J., Duffy D.L., Kroes H.Y., Martin N.G., Boomsma D.I., Campbell M., Coulthard M.G., Whitelaw E., Chong S. Am. J. Hum. Genet. 79:155-162(2006) [PubMed: 16773576] [Abstract] Cited for: INVOLVEMENT IN CAUDAL DUPLICATION ANOMALY.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

AF009674 mRNA. Translation: AAC51624.1. Different initiation.
AE006463 Genomic DNA. Translation: AAK61224.1.
Z69667, AC005202, Z99754 Genomic DNA. Translation: CAI95589.2.
Z69667, AC005202, Z99754 Genomic DNA. Translation: CAI95590.2.
Z99754, AC005202, Z69667 Genomic DNA. Translation: CAI95600.2.
Z99754, AC005202, Z69667 Genomic DNA. Translation: CAI95601.2.
BC017447 mRNA. Translation: AAH17447.1.
BC044648 mRNA. Translation: AAH44648.1.

IPI

IPI00747002.
IPI00748214.

RefSeq

NP_003493.1.
NP_851393.1.

UniGene

Hs.592082

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1DK8	X-ray	1.57	A	74-220	[»]
1EMU	X-ray	1.90	A	80-211	[»]
1O9U	X-ray	2.40	B	383-400	[»]

SMR

O15169. Positions 779-862.

ModBase

Search...

Protein-protein interaction databases

IntAct

O15169. 11 interactions.

STRING

O15169.

PTM databases

PhosphoSite

O15169.

Proteomic databases

PRIDE

O15169.

Genome annotation databases

Ensembl

ENST00000262320; ENSP00000262320; ENSG00000103126; Homo sapiens. [Genome view]
ENST00000354866; ENSP00000346935; ENSG00000103126; Homo sapiens. [Genome view]
ENST00000421566; ENSP00000405532; ENSG00000103126; Homo sapiens. [Genome view]
ENST00000457798; ENSP00000416835; ENSG00000103126; Homo sapiens. [Genome view]

GeneID

8312.

KEGG

hsa:8312.

UCSC

uc002cgp.1. human.
uc002cgq.1. human.

Organism-specific databases

CTD

8312.

GeneCards

GC16M000277.

HGNC

HGNC:903. AXIN1.

HPA

CAB012987.

MIM

114550. phenotype.
603816. gene.
607864. phenotype.

Orphanet

1756. Caudal duplication.

PharmGKB

PA25195.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

O15169.

HOVERGEN

O15169.

OMA

PGHRSPD.

Enzyme and pathway databases

Pathway_Interaction_DB

wnt_canonical_pathway. Canonical Wnt signaling pathway.
ps1pathway. Presenilin action in Notch and Wnt signaling.
tgfbrpathway. TGF-beta receptor signaling.

Reactome

REACT_11045. Signaling by Wnt.

Gene expression databases

ArrayExpress

O15169.

Bgee

O15169.

CleanEx

HS_AXIN1.

Genevestigator

O15169.

GermOnline

ENSG00000103126. Homo sapiens.

Family and domain databases

InterPro

IPR014936. Axin_b-cat_bd.
IPR001158. DIX.
IPR000342. Regulat_G_prot_signal.
[Graphical view]

Pfam

PF08833. Axin_b-cat_bind. 1 hit.
PF00778. DIX. 1 hit.
PF00615. RGS. 1 hit.
[Graphical view]

PRINTS

PR01301. RGSPROTEIN.

ProDom

PD003639. DIX. 1 hit.
PD001580. Regl_Gprotein. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00021. DAX. 1 hit.
SM00315. RGS. 1 hit.
[Graphical view]

PROSITE

PS50841. DIX. 1 hit.
PS50132. RGS. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

31127.

SOURCE

Search...

Entry information

Entry name

AXN1_HUMAN

Accession

Primary (citable) accession number: O15169
Secondary accession number(s): Q4TT26 , Q4TT27, Q86YA7, Q8WVW6, Q96S28

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 2000
Last sequence update:	May 10, 2002
Last modified:	November 3, 2009
This is version 111 of the entry and version 2 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.