AXIN1

This gene encodes a cytoplasmic protein which contains a regulation of G-protein signaling (RGS) domain and a dishevelled and axin (DIX) domain. The encoded protein interacts with adenomatosis polyposis coli, catenin beta-1, glycogen synthase kinase 3 beta, protein phosphate 2, and itself. This protein functions as a negative regulator of the wingless-type MMTV integration site family, member 1 (WNT) signaling pathway and can induce apoptosis. The crystal structure of a portion of this protein, alone and in a complex with other proteins, has been resolved. Mutations in this gene have been associated with hepatocellular carcinoma, hepatoblastomas, ovarian endometriod adenocarcinomas, and medullablastomas. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

Full Name

Axin 1

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).

Biological Process

Activation of protein kinase activity Source: BHF-UCL
Apoptotic process Source: UniProtKB-KW
Beta-catenin destruction complex assembly Source: Reactome
Beta-catenin destruction complex disassembly Source: Reactome
Cellular protein-containing complex assembly Source: BHF-UCL
Multicellular organism development Source: UniProtKB-KW
Negative regulation of canonical Wnt signaling pathway Source: BHF-UCL
Positive regulation of canonical Wnt signaling pathway Source: Reactome
Positive regulation of JNK cascade Source: UniProtKB
Positive regulation of peptidyl-serine phosphorylation Source: BHF-UCL
Positive regulation of peptidyl-threonine phosphorylation Source: BHF-UCL
Positive regulation of protein catabolic process Source: BHF-UCL
Positive regulation of protein phosphorylation Source: BHF-UCL
Positive regulation of protein ubiquitination Source: BHF-UCL
Positive regulation of transcription, DNA-templated Source: BHF-UCL
Positive regulation of ubiquitin-dependent protein catabolic process Source: BHF-UCL
Positive regulation of ubiquitin-protein transferase activity Source: BHF-UCL
Regulation of intracellular estrogen receptor signaling pathway Source: Reactome
Regulation of Wnt signaling pathway Source: Reactome
Wnt signaling pathway Source: Reactome

Cellular Location

Cell membrane; Cytoplasm; Nucleus; Membrane. MACF1 is required for its translocation to cell membrane (By similarity). On UV irradiation, translocates to the nucleus and colocalizes with DAAX (PubMed:17210684).

Involvement in disease

Hepatocellular carcinoma (HCC): 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.
Caudal duplication anomaly (CADUA): A condition characterized by the occurrence of duplications of different organs in the caudal region.

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.
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.
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.