UniProt functional annotation for O15169



	UniProt functional annotation for O15169

UniProt code: O15169.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Component of the beta-catenin destruction complex required for regulating CTNNB1 levels through phosphorylation and ubiquitination, and modulating Wnt-signaling (PubMed:12192039, PubMed:27098453). 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 (PubMed:12192039). In Wnt signaling, probably facilitates the phosphorylation of CTNNB1 and APC by GSK3B (PubMed:12192039). Likely to function as a tumor suppressor. Enhances TGF-beta signaling by recruiting the RNF111 E3 ubiquitin ligase and promoting the degradation of inhibitory SMAD7 (PubMed:16601693). Also component of the AXIN1-HIPK2-TP53 complex which controls cell growth, apoptosis and development (PubMed:17210684). Facilitates the phosphorylation of TP53 by HIPK2 upon ultraviolet irradiation (PubMed:17210684). {ECO:0000269|PubMed:12192039, ECO:0000269|PubMed:16601693, ECO:0000269|PubMed:17210684, ECO:0000269|PubMed:27098453}.

Subunit: Homodimer (By similarity). Interacts with ZBED3; the interaction is direct, enhanced by protein kinase GSK3B and casein kinase CSNK1E activities and decreases GSK3B-induced beta-catenin serine and threonine phosphorylations (By similarity). Component of the beta-catenin destruction complex, containing at least, CTNNB1, an axin and GSK3B, that regulates CTNNB1 protein levels through phosphorylation and ubiquitination. Interacts with CTNNB1 (via the armadillo repeats 2- 7). Interacts with GSK3B; the interaction hyperphosphorylates CTNNB1 leading to its ubiquitination and destruction (PubMed:17318175, PubMed:12554650). Component of the AXIN1-HIPK2-TP53 complex (PubMed:17210684). Interacts directly in the complex with TP53 and HIPK2 (PubMed:17210684). 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 (PubMed:17210684). Also binds APC, SMAD6, SMAD7 and RNF111 (PubMed:16601693, PubMed:10811618). Interacts with DIXDC1; prevents interaction with MAP3K1 (PubMed:15262978). Interacts with MAP3K4 (PubMed:15262978). Interacts with ANKRD6 and AIDA (By similarity). Interacts with MDFI; the interaction decreases AXIN1-mediated JUN N- terminal kinase (JNK) activation (PubMed:12192039). Interacts with MDFIC; the interaction inhibits beta-cateninin-mediated signaling and AXIN1-mediated JUN N-terminal kinase (JNK) activation (PubMed:12192039). Interacts with LRP5 (via its phosphorylated PPPSP motifs); the interaction is stimulated by WNT1 and GSK3B and activates beta-catenin signaling (PubMed:11336703). Interacts (via the C- terminal) with PPP1CA; the interaction dephosphorylates AXIN1 and regulates interaction with GSK3B (PubMed:9920888). Interacts with PPP2CA; the interaction dephosphorylates AXIN1 (PubMed:9920888). Interacts with MACF1 (By similarity). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B (By similarity). Interacts with TNKS (PubMed:19759537, PubMed:21478859, PubMed:21799911). Interacts with DAB2; the interaction is mutually exclusive with the AXIN1:PPP1CA interaction (PubMed:12805222). Interacts with WDR26 (PubMed:27098453). Interacts with GID8 (PubMed:28829046). {ECO:0000250|UniProtKB:O35625, ECO:0000250|UniProtKB:O70239, ECO:0000269|PubMed:10811618, ECO:0000269|PubMed:11336703, ECO:0000269|PubMed:12192039, ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:12805222, ECO:0000269|PubMed:15262978, ECO:0000269|PubMed:16601693, ECO:0000269|PubMed:17210684, ECO:0000269|PubMed:17318175, ECO:0000269|PubMed:19759537, ECO:0000269|PubMed:21478859, ECO:0000269|PubMed:21799911, ECO:0000269|PubMed:27098453, ECO:0000269|PubMed:28829046, ECO:0000269|PubMed:9920888}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:16601693}. Nucleus {ECO:0000269|PubMed:17210684}. Membrane {ECO:0000250|UniProtKB:O35625}. Cell membrane {ECO:0000250|UniProtKB:O35625}. Note=MACF1 is required for its translocation to cell membrane (By similarity). On UV irradiation, translocates to the nucleus and colocalizes with DAAX (PubMed:17210684). {ECO:0000250|UniProtKB:O35625, ECO:0000269|PubMed:17210684}.

Tissue specificity: Ubiquitously expressed.

Domain: The tankyrase-binding motif (also named TBD) is required for interaction with tankyrase TNKS and TNKS2. {ECO:0000269|PubMed:19759537}.

Ptm: 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. {ECO:0000269|PubMed:17318175, ECO:0000269|PubMed:9920888}.

Ptm: ADP-ribosylated by tankyrase TNKS and TNKS2. Poly-ADP-ribosylated protein is recognized by RNF146, followed by ubiquitination at 'Lys-48' and subsequent activation of the Wnt signaling pathway. {ECO:0000269|PubMed:21383061}.

Ptm: Ubiquitinated by RNF146 when poly-ADP-ribosylated, leading to its degradation and subsequent activation of the Wnt signaling pathway. Sumoylation at Lys-857 and Lys-860 prevents ubiquitination and degradation. Sumoylation is required for AXIN1-mediated JNK activation. 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. {ECO:0000269|PubMed:18632848, ECO:0000269|PubMed:21383061}.

Disease: Hepatocellular carcinoma (HCC) [MIM:114550]: A primary malignant neoplasm of epithelial liver cells. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. {ECO:0000269|PubMed:12101426}. Note=The gene represented in this entry is involved in disease pathogenesis.

Disease: Caudal duplication anomaly (CADUA) [MIM:607864]: A condition characterized by the occurrence of duplications of different organs in the caudal region. {ECO:0000269|PubMed:16773576}. Note=The disease is caused by variants affecting the gene represented in this entry. Caudal duplication anomaly is associated with hypermethylation of the AXIN1 promoter.

Sequence caution: Sequence=AAC51624.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Component of the beta-catenin destruction complex required for regulating CTNNB1 levels through phosphorylation and ubiquitination, and modulating Wnt-signaling (PubMed:12192039, PubMed:27098453). 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 (PubMed:12192039). In Wnt signaling, probably facilitates the phosphorylation of CTNNB1 and APC by GSK3B (PubMed:12192039). Likely to function as a tumor suppressor. Enhances TGF-beta signaling by recruiting the RNF111 E3 ubiquitin ligase and promoting the degradation of inhibitory SMAD7 (PubMed:16601693). Also component of the AXIN1-HIPK2-TP53 complex which controls cell growth, apoptosis and development (PubMed:17210684). Facilitates the phosphorylation of TP53 by HIPK2 upon ultraviolet irradiation (PubMed:17210684). {ECO:0000269\|PubMed:12192039, ECO:0000269\|PubMed:16601693, ECO:0000269\|PubMed:17210684, ECO:0000269\|PubMed:27098453}.


Subunit:		Homodimer (By similarity). Interacts with ZBED3; the interaction is direct, enhanced by protein kinase GSK3B and casein kinase CSNK1E activities and decreases GSK3B-induced beta-catenin serine and threonine phosphorylations (By similarity). Component of the beta-catenin destruction complex, containing at least, CTNNB1, an axin and GSK3B, that regulates CTNNB1 protein levels through phosphorylation and ubiquitination. Interacts with CTNNB1 (via the armadillo repeats 2- 7). Interacts with GSK3B; the interaction hyperphosphorylates CTNNB1 leading to its ubiquitination and destruction (PubMed:17318175, PubMed:12554650). Component of the AXIN1-HIPK2-TP53 complex (PubMed:17210684). Interacts directly in the complex with TP53 and HIPK2 (PubMed:17210684). 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 (PubMed:17210684). Also binds APC, SMAD6, SMAD7 and RNF111 (PubMed:16601693, PubMed:10811618). Interacts with DIXDC1; prevents interaction with MAP3K1 (PubMed:15262978). Interacts with MAP3K4 (PubMed:15262978). Interacts with ANKRD6 and AIDA (By similarity). Interacts with MDFI; the interaction decreases AXIN1-mediated JUN N- terminal kinase (JNK) activation (PubMed:12192039). Interacts with MDFIC; the interaction inhibits beta-cateninin-mediated signaling and AXIN1-mediated JUN N-terminal kinase (JNK) activation (PubMed:12192039). Interacts with LRP5 (via its phosphorylated PPPSP motifs); the interaction is stimulated by WNT1 and GSK3B and activates beta-catenin signaling (PubMed:11336703). Interacts (via the C- terminal) with PPP1CA; the interaction dephosphorylates AXIN1 and regulates interaction with GSK3B (PubMed:9920888). Interacts with PPP2CA; the interaction dephosphorylates AXIN1 (PubMed:9920888). Interacts with MACF1 (By similarity). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B (By similarity). Interacts with TNKS (PubMed:19759537, PubMed:21478859, PubMed:21799911). Interacts with DAB2; the interaction is mutually exclusive with the AXIN1:PPP1CA interaction (PubMed:12805222). Interacts with WDR26 (PubMed:27098453). Interacts with GID8 (PubMed:28829046). {ECO:0000250\|UniProtKB:O35625, ECO:0000250\|UniProtKB:O70239, ECO:0000269\|PubMed:10811618, ECO:0000269\|PubMed:11336703, ECO:0000269\|PubMed:12192039, ECO:0000269\|PubMed:12554650, ECO:0000269\|PubMed:12805222, ECO:0000269\|PubMed:15262978, ECO:0000269\|PubMed:16601693, ECO:0000269\|PubMed:17210684, ECO:0000269\|PubMed:17318175, ECO:0000269\|PubMed:19759537, ECO:0000269\|PubMed:21478859, ECO:0000269\|PubMed:21799911, ECO:0000269\|PubMed:27098453, ECO:0000269\|PubMed:28829046, ECO:0000269\|PubMed:9920888}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:16601693}. Nucleus {ECO:0000269\|PubMed:17210684}. Membrane {ECO:0000250\|UniProtKB:O35625}. Cell membrane {ECO:0000250\|UniProtKB:O35625}. Note=MACF1 is required for its translocation to cell membrane (By similarity). On UV irradiation, translocates to the nucleus and colocalizes with DAAX (PubMed:17210684). {ECO:0000250\|UniProtKB:O35625, ECO:0000269\|PubMed:17210684}.
Tissue specificity:		Ubiquitously expressed.
Domain:		The tankyrase-binding motif (also named TBD) is required for interaction with tankyrase TNKS and TNKS2. {ECO:0000269\|PubMed:19759537}.
Ptm:		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. {ECO:0000269\|PubMed:17318175, ECO:0000269\|PubMed:9920888}.
Ptm:		ADP-ribosylated by tankyrase TNKS and TNKS2. Poly-ADP-ribosylated protein is recognized by RNF146, followed by ubiquitination at 'Lys-48' and subsequent activation of the Wnt signaling pathway. {ECO:0000269\|PubMed:21383061}.
Ptm:		Ubiquitinated by RNF146 when poly-ADP-ribosylated, leading to its degradation and subsequent activation of the Wnt signaling pathway. Sumoylation at Lys-857 and Lys-860 prevents ubiquitination and degradation. Sumoylation is required for AXIN1-mediated JNK activation. 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. {ECO:0000269\|PubMed:18632848, ECO:0000269\|PubMed:21383061}.
Disease:		Hepatocellular carcinoma (HCC) [MIM:114550]: A primary malignant neoplasm of epithelial liver cells. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. {ECO:0000269\|PubMed:12101426}. Note=The gene represented in this entry is involved in disease pathogenesis.
Disease:		Caudal duplication anomaly (CADUA) [MIM:607864]: A condition characterized by the occurrence of duplications of different organs in the caudal region. {ECO:0000269\|PubMed:16773576}. Note=The disease is caused by variants affecting the gene represented in this entry. Caudal duplication anomaly is associated with hypermethylation of the AXIN1 promoter.
Sequence caution:		Sequence=AAC51624.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};