Short name=Protein APC
Alternative name(s):
Deleted in polyposis 2.5
Gene names
Name: APC
Synonyms: DP2.5
Function
Tumor suppressor. Promotes rapid degradation of CTNNB1 and participates in Wnt signaling as a negative regulator. APC activity is correlated with its phosphorylation state. Activates the GEF activity of SPATA13 and ARHGEF4. Plays a role in hepatocyte growth factor (HGF)-induced cell migration. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Acts as a mediator of ERBB2-dependent stabilization of microtubules at the cell cortex. It is required for the localization of MACF1 to the cell membrane and this localization of MACF1 is critical for its function in microtubule stabilization. Ref.3 Ref.16 Ref.22 Ref.23 Ref.25
Subunit structure
Forms homooligomers and heterooligomers with APC2. Interacts with DIAPH1 and DIAPH2 By similarity. Interacts with PDZ domains of DLG1 and DLG3. Associates with catenins. Binds axin. Interacts with ARHGEF4 (via N-terminus). Interacts with MAPRE1 (via C-terminus); probably required for APC targeting to the growing microtubule plus ends. Interacts with MAPRE2 and MAPRE3 (via C-terminus). Found in a complex consisting of ARHGEF4, APC and CTNNB1. Interacts with SCRIB; may mediate APC targeting to adherens junctions of epithelial cells. Interacts with SPATA13 (via N-terminus and SH3 domain). Interacts with ASAP1 (via SH3 domain). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B By similarity. Interacts at the cell membrane with AMER1 and AMER2 (via ARM repeats). Ref.3 Ref.8 Ref.9 Ref.11 Ref.12 Ref.15 Ref.16 Ref.21 Ref.27 Ref.29
Subcellular location
Cell junction › adherens junction. Cytoplasm › cytoskeleton. Cell projection › lamellipodium. Cell projection › ruffle membrane. Cytoplasm. Cell membrane. Note: Associated with the microtubule network at the growing distal tip of microtubules. Accumulates in the lamellipodium and ruffle membrane in response to hepatocyte growth factor (HGF) treatment. The MEMO1-RHOA-DIAPH1 signaling pathway controls localization of the phosophorylated form to the cell membrane. Ref.3 Ref.15 Ref.21 Ref.23 Ref.25
Tissue specificity
Expressed in a variety of tissues.
Domain
The microtubule tip localization signal (MtLS) motif; mediates interaction with MAPRE1 and targeting to the growing microtubule plus ends By similarity. Ref.36
Post-translational modification
Phosphorylated by GSK3B.
Ubiquitinated, leading to its degradation by the proteasome. Ubiquitination is facilitated by Axin. Deubiquitinated by ZRANB1/TRABID. Ref.13 Ref.17
Involvement in disease
Familial adenomatous polyposis (FAP) [MIM:175100]: A cancer predisposition syndrome characterized by adenomatous polyps of the colon and rectum, but also of upper gastrointestinal tract (ampullary, duodenal and gastric adenomas). This is a viciously premalignant disease with one or more polyps progressing through dysplasia to malignancy in untreated gene carriers with a median age at diagnosis of 40 years.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.7 Ref.10 Ref.37 Ref.38 Ref.39 Ref.40 Ref.41 Ref.42 Ref.46 Ref.53
Hereditary desmoid disease (HDD) [MIM:135290]: Autosomal dominant trait with 100% penetrance and possible variable expression among affected relatives. HDD patients show multifocal fibromatosis of the paraspinal muscles, breast, occiput, arms, lower ribs, abdominal wall, and mesentery. Desmoid tumors appears also as a complication of familial adenomatous polyposis.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.7 Ref.10
Medulloblastoma (MDB) [MIM:155255]: Malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children.
Note: The gene represented in this entry may be involved in disease pathogenesis. Ref.7 Ref.10 Ref.54
Mismatch repair cancer syndrome (MMRCS) [MIM:276300]: Autosomal dominant disorder characterized by malignant tumors of the brain associated with multiple colorectal adenomas. Skin features include sebaceous cysts, hyperpigmented and cafe au lait spots.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.7 Ref.10 Ref.44
Gastric cancer (GASC) [MIM:613659]: A malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease.
Note: The gene represented in this entry may be involved in disease pathogenesis. Ref.7 Ref.10
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.
Note: The gene represented in this entry may be involved in disease pathogenesis. Ref.7 Ref.10
Miscellaneous
APC mutations have led to some interesting observations. (1) the great majority of the mutations found to date would result in truncation of the APC product. (2) almost all the mutations have occurred within the first half of the coding sequence, and somatic mutations in colorectal tumors are further clustered in a particular region, called MCR (mutation cluster region). (3) most identified point mutations in the APC gene are transitions from cytosine to other nucleotides. (4) the location of germline mutations tends to correlate with the number of colorectal polyps in FAP patients. Inactivation of both alleles of the APC gene seems to be required as an early event to develop most adenomas and carcinomas in the colon and rectum as well as some of those in the stomach.
Sequence similarities
Belongs to the adenomatous polyposis coli (APC) family.
Contains 7 ARM repeats.
