Human Gene APC (ENST00000257430.9_5) from GENCODE V47lift37
Description: 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. Associates with both microtubules and actin filaments, components of the cytoskeleton (PubMed:17293347). Plays a role in mediating the organization of F- actin into ordered bundles (PubMed:17293347). Functions downstream of Rho GTPases and DIAPH1 to selectively stabilize microtubules (By similarity). 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. (from UniProt P25054) Gencode Transcript: ENST00000257430.9_5 Gencode Gene: ENSG00000134982.19_15 Transcript (Including UTRs) Position: hg19 chr5:112,073,582-112,181,936 Size: 108,355 Total Exon Count: 16 Strand: + Coding Region Position: hg19 chr5:112,090,588-112,179,823 Size: 89,236 Coding Exon Count: 15
ID:APC_HUMAN DESCRIPTION: RecName: Full=Adenomatous polyposis coli protein; Short=Protein APC; AltName: Full=Deleted in polyposis 2.5; 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. SUBUNIT: 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 FAM123A and FAM123B (via ARM repeats). INTERACTION: P35222:CTNNB1; NbExp=7; IntAct=EBI-727707, EBI-491549; Q02248:Ctnnb1 (xeno); NbExp=8; IntAct=EBI-727707, EBI-397872; Q15691:MAPRE1; NbExp=4; IntAct=EBI-727707, EBI-1004115; 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. 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). PTM: Phosphorylated by GSK3B. PTM: Ubiquitinated, leading to its degradation by the proteasome. Ubiquitination is facilitated by Axin. Deubiquitinated by ZRANB1/TRABID. DISEASE: Defects in APC are a cause of familial adenomatous polyposis (FAP) [MIM:175100]; which includes also Gardner syndrome (GS). FAP and GS contribute to tumor development in patients with uninherited forms of colorectal cancer. FAP is 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. DISEASE: Defects in APC are a cause of hereditary desmoid disease (HDD) [MIM:135290]; also known as familial infiltrative fibromatosis (FIF). HDD is an 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. DISEASE: Defects in APC are a cause of medulloblastoma (MDB) [MIM:155255]. MDB is a malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children. Although the majority of medulloblastomas occur sporadically, some manifest within familial cancer syndromes such as Turcot syndrome and basal cell nevus syndrome (Gorlin syndrome). DISEASE: Defects in APC are a cause of mismatch repair cancer syndrome (MMRCS) [MIM:276300]; also known as Turcot syndrome or brain tumor-polyposis syndrome 1 (BTPS1). MMRCS is an 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. DISEASE: Defects in APC are a cause of gastric cancer (GASC) [MIM:613659]; also called gastric cancer intestinal or stomach cancer. Gastric cancer is 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. DISEASE: Defects in APC are a cause of hepatocellular carcinoma (HCC) [MIM:114550]. This defect includes also the disease entity termed hepatoblastoma. 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. SIMILARITY: Belongs to the adenomatous polyposis coli (APC) family. SIMILARITY: Contains 7 ARM repeats. WEB RESOURCE: Name=Colon cancer gene variant databases Adenomatous Polyposis Coli (APC); Note=Leiden Open Variation Database (LOVD); URL="http://chromium.liacs.nl/LOVD2/colon_cancer/home.php?select_db=APC"; WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/APC118.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/APC"; WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and polymorphism database; URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=APC"; WEB RESOURCE: Name=Wikipedia; Note=APC entry; URL="http://en.wikipedia.org/wiki/APC_%28gene%29";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
Pfam Domains: PF00514 - Armadillo/beta-catenin-like repeat PF05923 - APC repeat PF05924 - SAMP Motif PF05937 - EB-1 Binding Domain PF05956 - APC basic domain PF05972 - APC 15 residue motif PF11414 - Adenomatous polyposis coli tumour suppressor protein PF16629 - Armadillo-associated region on APC PF16630 - Unstructured region on APC between 1st and 2nd catenin-bdg motifs PF16633 - Unstructured region on APC between 1st two creatine-rich regions PF16634 - Unstructured region on APC between APC_crr and SAMP PF16635 - Unstructured region on APC between SAMP and APC_crr PF16636 - Unstructured region on APC between APC_crr regions 5 and 6 PF16689 - Coiled-coil N-terminus of APC, dimerisation domain PF18797 - Adenomatous polyposis coli (APC) repeat
ModBase Predicted Comparative 3D Structure on P25054
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
BioCarta from NCI Cancer Genome Anatomy Project h_tgfbPathway - TGF beta signaling pathway h_gsk3Pathway - Inactivation of Gsk3 by AKT causes accumulation of b-catenin in Alveolar Macrophages h_ps1Pathway - Presenilin action in Notch and Wnt signaling h_alkPathway - ALK in cardiac myocytes h_pitx2Pathway - Multi-step Regulation of Transcription by Pitx2 h_wntPathway - WNT Signaling Pathway
Reactome (by CSHL, EBI, and GO)
Protein P25054 (Reactome details) participates in the following event(s):
R-NUL-209144 Human APC is finally phosphorylated by Murine GSK3beta R-NUL-209065 Human APC is further phosphorylated by Murine CKIepsilon R-NUL-209060 Human APC is further phosphorylated by Murine GSK3beta R-NUL-209132 Human APC is initially phosphorylated by Murine CKIepsilon R-HSA-202947 Caspase mediated cleavage of APC R-HSA-5246693 APC is K63-polyubiquitinated R-HSA-195251 Assembly of the destruction complex R-HSA-6781905 ZRANB1 binds APC R-HSA-201685 Beta-catenin is released from the destruction complex R-HSA-195280 Dissociation of beta-catenin from Axin and association of beta catenin with phospho-(20 aa) APC in the detruction complex R-HSA-195275 Phosphorylation of APC component of the destruction complex R-HSA-2130279 Association of beta-catenin with the RBX1:SCF(beta-TrCP1) ubiquitin ligase complex R-HSA-5229343 AXIN is phosphorylated in the destruction complex R-HSA-195304 Association of beta-catenin with the destruction complex R-HSA-2130286 Multi-ubiquitination of phospho-beta-catenin by RBX1:SCF(beta-TrCP1) R-HSA-195287 Phosphorylation of phospho-(Ser45 ) at Thr 41 by GSK-3 R-HSA-195318 Phosphorylation of beta-catenin at Ser45 by CK1 alpha R-HSA-195300 Phosphorylation of phospho-(Ser45,Thr41,Ser37) at Ser33 by GSK-3 R-HSA-195283 Phosphorylation of phospho- (Ser45, Thr41) beta-catenin at Ser37 by GSK-3 R-HSA-111465 Apoptotic cleavage of cellular proteins R-HSA-195253 Degradation of beta-catenin by the destruction complex R-HSA-3769402 Deactivation of the beta-catenin transactivating complex R-HSA-5467340 AXIN missense mutants destabilize the destruction complex R-HSA-5467348 Truncations of AMER1 destabilize the destruction complex R-HSA-5689896 Ovarian tumor domain proteases R-HSA-4641262 Disassembly of the destruction complex and recruitment of AXIN to the membrane R-HSA-75153 Apoptotic execution phase R-HSA-195721 Signaling by WNT R-HSA-201681 TCF dependent signaling in response to WNT R-HSA-5467337 APC truncation mutants have impaired AXIN binding R-HSA-5467333 APC truncation mutants are not K63 polyubiquitinated R-HSA-4839735 AXIN mutants destabilize the destruction complex, activating WNT signaling R-HSA-4839748 AMER1 mutants destabilize the destruction complex R-HSA-5688426 Deubiquitination R-HSA-109581 Apoptosis R-HSA-5339716 Misspliced GSK3beta mutants stabilize beta-catenin R-HSA-162582 Signal Transduction R-HSA-4839744 truncated APC mutants destabilize the destruction complex R-HSA-5358751 S45 mutants of beta-catenin aren't phosphorylated R-HSA-5358752 T41 mutants of beta-catenin aren't phosphorylated R-HSA-5358749 S37 mutants of beta-catenin aren't phosphorylated R-HSA-5358747 S33 mutants of beta-catenin aren't phosphorylated R-HSA-196299 Beta-catenin phosphorylation cascade R-HSA-4791275 Signaling by WNT in cancer R-HSA-597592 Post-translational protein modification R-HSA-5357801 Programmed Cell Death R-HSA-4839743 phosphorylation site mutants of CTNNB1 are not targeted to the proteasome by the destruction complex R-HSA-5663202 Diseases of signal transduction R-HSA-392499 Metabolism of proteins R-HSA-1643685 Disease
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
