O35625 (AXIN1_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified November 13, 2013. Version 134. History...
Names and origin
|Protein names||Recommended name:|
Axis inhibition protein 1
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||863 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Component of the beta-catenin destruction complex required for regulating CTNNB1 levels through phosphorylation and ubiquitination, and modulating Wnt-signaling By similarity. Controls dorsoventral patterning via two opposing effects; down-regulates CTNNB1 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 CTNNB1 and APC by GSK3B. Likely to function as a tumor suppressor. Facilitates the phosphorylation of TP53 by HIPK2 upon ultraviolet irradiation. Enhances TGF-beta signaling by recruiting the RNF111 E3 ubiquitin ligase and promoting the degradation of inhibitory SMAD7 By similarity. Also component of the AXIN1-HIPK2-TP53 complex which controls cell growth, apoptosis and development. Ref.6 Ref.8 Ref.11
Homodimer. Component of the beta-catenin destruction complex, containing at least CTNNB1, an axin and GSK3B, that regulates CTNNB1 protein levels through phosphorylation and ubiquitination By similarity. Interacts with GSK3B; the interaction hyperphosphorylates CTNNB1 leading to its ubiquitination and destruction. Interacts with DAXX; the interaction stimulates the interaction of DAXX with TP53, stimulates 'Ser-46' phosphorylation of TP53 and induces cell death on UV irradiation. Also interacts with APC, RNF111, SMAD6 and SMAD7. Interacts (via the C-terminal) with PPP1CA; the interaction dephosphorylates AXIN1 and regulates interaction with GSK3B. Interacts with PPP2CA; the interaction dephosphorylates AXIN1. Interacts with MDFI; the interaction decreases AXIN1-mediated JUN N-terminal kinase (JNK) activation. Interacts with MDFIC; the interaction inhibits beta-cateninin-mediated signaling and AXIN1-mediated JUN N-terminal kinase (JNK) activation By similarity. Binds ANKRD6, PIAS1, PIAS2, PIAS4, SUMO1, MAP3K1 and MAP3K4. Component of the AXIN1-HIPK2-TP53 complex. Interacts directly in the complex with TP53 and HIPK2. Interacts with DIXDC1; the interaction prevents interaction with MAP3K1. Interacts with AIDA; the interaction blocks the AXIN1-mediated JNK activation through disrupting AXIN1 homodimerization and Wnt signaling. Interacts with LRP5 (via its phosphorylated PPPSP motifs); the interaction is stimulated by WNT1 and GSK3B and activates beta-catenin signaling. Interacts with CTNNB1 (via the armadillo repeats 2-7). Interacts with MACF1 By similarity. Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B By similarity. Interacts with TNKS By similarity. Interacts with DAB2; the interaction is mutually exclusive with the AXIN1:PPP1CA interaction. Interacts with ZBED3 (via PPPSP motif); the interaction is direct, enhanced by protein kinase GSK3B and casein kinase CSNK1E activities and decreases GSK3B-induced beta-catenin serine and threonine phosphorylations. Ref.3 Ref.4 Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.11 Ref.13 Ref.14
Cytoplasm. Nucleus By similarity. Cell membrane. Membrane. Note: On UV irradiation, translocates to the nucleus and colocalizes with DAAX By similarity. MACF1 is required for its translocation to cell membrane. Ref.10 Ref.13
Expressed in embryonic stem cells.
Widely expressed at E10.5 to E16.5 day.
The tankyrase-binding motif (also named TBD) is required for interaction with tankyrase TNKS and TNKS2 By similarity.
Phosphorylation and dephosphorylation of AXIN1 regulates assembly and function of the beta-catenin complex. Phosphorylated by CK1 and GSK3B. Dephosphorylated by PPP1CA and PPP2CA. Phosphorylation by CK1 enhances binding of GSK3B to AXIN1 By similarity. Also phosphorylated by CDK2 which regulates interaction with CTNBB1. Ref.3 Ref.7
ADP-ribosylated by tankyrase TNKS and TNKS2. Poly-ADP-ribosylated protein is recognized by RNF146, followed by ubiquitination and subsequent activation of the Wnt signaling pathway By similarity.
Ubiquitinated by RNF146 when poly-ADP-ribosylated, leading to its degradation and subsequent activation of the Wnt signaling pathway. Deubiquitinated by USP34, deubiquitinated downstream of beta-catenin stabilization step: deubiquitination is important for nuclear accumulation during Wnt signaling to positively regulate beta-catenin (CTNBB1)-mediated transcription By similarity. Sumoylation at Lys-858 and Lys-861 prevents ubiquitination and degradation. Sumoylation is required for AXIN1-mediated JNK activation.
Contains 1 DIX domain.
Contains 1 RGS domain.
The sequence AAC53285.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.
|CTNNB1||P35222||2||EBI-2365912,EBI-491549||From a different organism.|
|GSK3B||P49841||4||EBI-2365912,EBI-373586||From a different organism.|
|TNKS||O95271||4||EBI-2365912,EBI-1105254||From a different organism.|
|This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform 1 (identifier: O35625-1) |
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: O35625-2) |
The sequence of this isoform differs from the canonical sequence as follows:
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 863||863||Axin-1||PRO_0000220889|
|Domain||88 – 211||124||RGS|
|Domain||781 – 863||83||DIX|
|Region||209 – 338||130||Interaction with TP53|
|Region||348 – 432||85||Interaction with GSK3B By similarity|
|Region||433 – 501||69||Interaction with beta-catenin By similarity|
|Region||505 – 758||254||Interaction with RNF111 By similarity|
|Region||572 – 790||219||Interaction with PPP2CA By similarity|
|Region||678 – 753||76||Interaction with HIPK2|
|Motif||20 – 29||10||Tankyrase-binding motif|
Amino acid modifications
|Modified residue||75||1||Phosphoserine; by CK1 By similarity|
|Modified residue||77||1||Phosphoserine; by CK1 By similarity|
|Modified residue||217||1||Phosphoserine; by CK1 By similarity|
|Modified residue||468||1||Phosphoserine; by CK1 By similarity|
|Modified residue||480||1||Phosphothreonine; by GSK3-beta Probable|
|Modified residue||485||1||Phosphoserine; by GSK3-beta Ref.3|
|Modified residue||492||1||Phosphoserine Ref.3|
|Cross-link||858||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.6 Ref.12|
|Cross-link||861||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.6 Ref.12|
|Alternative sequence||731 – 766||36||Missing in isoform 2.||VSP_000452|
|Mutagenesis||480||1||T → A: Greatly reduced GSK3B-mediated phosphorylation; when associated with A-485 and A-492. Ref.3|
|Mutagenesis||485||1||S → A: Greatly reduced GSK3B-mediated phosphorylation and large effect on the inhibitory activity in Wnt-signaling; when associated with A-480 and A-492. Ref.3|
|Mutagenesis||492||1||S → A: Greatly reduced GSK3B-mediated phosphorylation; when associated with A-480 and A-485. Ref.3|
|Mutagenesis||492||1||S → I: Little effect on inhibitory activity on Wnt-signaling. Ref.3|
|Mutagenesis||495||1||S → A: No effect on phosphorylation. Little effect on inhibitory activity on Wnt-signaling. Ref.3|
|Mutagenesis||858 – 863||6||Missing: Abolishes binding of PIAS1 and PIAS2. Dramatically reduces sumoylation and abolishes AXIN1-mediated JNK activation. No effect on homodimerization nor on Wnt-signaling. Ref.6 Ref.12|
|Mutagenesis||858||1||K → A: Decreased sumoylation followed by increased ubiquitination; when associated with A-861. Ref.12|
|Mutagenesis||861||1||K → A: Decreased sumoylation followed by increased ubiquitination; when associated with A-858. Ref.12|
|Sequence conflict||589||1||A → P in AAC53285. Ref.1|
|Sequence conflict||787||1||A → G in AAC53285. Ref.1|
|Sequence conflict||846||1||A → P in AAC53285. Ref.1|
Helix Strand Turn
|Beta strand||64 – 66||3|
|||"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 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. Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|||"A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expression."|
Jho E., Lomvardas S., Costantini F.
Biochem. Biophys. Res. Commun. 266:28-35(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-480; SER-485 AND SER-492, INTERACTION WITH CTNNB1, MUTAGENESIS OF THR-480; SER-485; SER-492 AND SER-495.
|||"Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway."|
Mao J., Wang J., Liu B., Pan W., Farr G.H. III, Flynn C., Yuan H., Takada S., Kimelman D., Li L., Wu D.
Mol. Cell 7:801-809(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH LRP5.
|||"The ankyrin repeat protein diversin recruits casein kinase Iepsilon to the beta-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling."|
Schwarz-Romond T., Asbrand C., Bakkers J., Kuehl M., Schaeffer H.J., Huelsken J., Behrens J., Hammerschmidt M., Birchmeier W.
Genes Dev. 16:2073-2084(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ANKRD6.
|||"SUMO-1 modification of the C-terminal KVEKVD of Axin is required for JNK activation but has no effect on Wnt signaling."|
Rui H.L., Fan E., Zhou H.M., Xu Z., Zhang Y., Lin S.C.
J. Biol. Chem. 277:42981-42986(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: SUMOYLATION AT LYS-858 AND LYS-861, INTERACTION WITH MAP3K1; SUMO1; PIAS1; PIAS2 AND PIAS4, FUNCTION, HOMODIMERIZATION, MUTAGENESIS OF 858-LYS--ASP-863.
|||"Cyclin-dependent kinase 2 regulates the interaction of Axin with beta-catenin."|
Kim S.I., Park C.S., Lee M.S., Kwon M.S., Jho E.H., Song W.K.
Biochem. Biophys. Res. Commun. 317:478-483(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION, INTERACTION WITH CTNNB1.
|||"Axin stimulates p53 functions by activation of HIPK2 kinase through multimeric complex formation."|
Rui Y., Xu Z., Lin S., Li Q., Rui H., Luo W., Zhou H.-M., Cheung P.-Y., Wu Z., Ye Z., Li P., Han J., Lin S.-C.
EMBO J. 23:4583-4594(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH TP53 AND HIPK2, IDENTIFICATION IN A COMPLEX WITH TP53 AND HIPK2.
|||"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] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DIXDC1; MAP3K1 AND MAP3K4.
|||"The role of microtubule actin cross-linking factor 1 (MACF1) in the Wnt signaling pathway."|
Chen H.J., Lin C.M., Lin C.S., Perez-Olle R., Leung C.L., Liem R.K.
Genes Dev. 20:1933-1945(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
|||"A beta-catenin-independent dorsalization pathway activated by Axin/JNK signaling and antagonized by aida."|
Rui Y., Xu Z., Xiong B., Cao Y., Lin S., Zhang M., Chan S.-C., Luo W., Han Y., Lu Z., Ye Z., Zhou H.-M., Han J., Meng A., Lin S.-C.
Dev. Cell 13:268-282(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, HOMODIMERIZATION, INTERACTION WITH AIDA.
|||"SUMOylation target sites at the C terminus protect Axin from ubiquitination and confer protein stability."|
Kim M.J., Chia I.V., Costantini F.
FASEB J. 22:3785-3794(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: SUMOYLATION AT LYS-858 AND LYS-861, MUTAGENESIS OF LYS-858 AND LYS-861.
|||"Identification of zinc-finger BED domain-containing 3 (Zbed3) as a novel Axin-interacting protein that activates Wnt/beta-catenin signaling."|
Chen T., Li M., Ding Y., Zhang L.S., Xi Y., Pan W.J., Tao D.L., Wang J.Y., Li L.
J. Biol. Chem. 284:6683-6689(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ZBED3, SUBCELLULAR LOCATION.
|||"Dab2 stabilizes Axin and attenuates Wnt/beta-catenin signaling by preventing protein phosphatase 1 (PP1)-Axin interactions."|
Jiang Y., Luo W., Howe P.H.
Oncogene 28:2999-3007(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DAB2.
|+||Additional computationally mapped references.|
|AF009011 mRNA. Translation: AAC53285.1. Different initiation.|
AC126438 Genomic DNA. No translation available.
AC140047 Genomic DNA. No translation available.
|RefSeq||NP_033863.2. NM_009733.2. |
3D structure databases
|SMR||O35625. Positions 74-220, 780-863. |
Protein-protein interaction databases
|IntAct||O35625. 20 interactions.|
Protocols and materials databases
Genome annotation databases
|MGI||MGI:1096327. Axin1. |
Gene expression databases
Family and domain databases
|Gene3D||184.108.40.206. 2 hits. |
|InterPro||IPR014936. Axin_b-cat-bd. |
|Pfam||PF08833. Axin_b-cat_bind. 1 hit. |
PF00778. DIX. 1 hit.
PF00615. RGS. 1 hit.
|PRINTS||PR01301. RGSPROTEIN. |
|SMART||SM00021. DAX. 1 hit. |
SM00315. RGS. 1 hit.
|SUPFAM||SSF48097. SSF48097. 1 hit. |
|PROSITE||PS50841. DIX. 1 hit. |
PS50132. RGS. 1 hit.
|Accession||Primary (citable) accession number: O35625|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|