Adenomatous polyposis coli

Last updated
APC
PBB Protein APC image.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases APC , BTPS2, DP2, DP2.5, DP3, GS, PPP1R46, adenomatous polyposis coli, WNT signaling pathway regulator, Genes
External IDs OMIM: 611731 MGI: 88039 HomoloGene: 30950 GeneCards: APC
Orthologs
SpeciesHumanMouse
Entrez

324

11789

Ensembl

ENSG00000134982

ENSMUSG00000005871

UniProt

P25054

Q61315

RefSeq (mRNA)

NM_001127511
NM_000038
NM_001127510

NM_007462
NM_001360979
NM_001360980

RefSeq (protein)

n/a

Location (UCSC)n/a Chr 18: 34.22 – 34.32 Mb
PubMed search [2] [3]
Wikidata
View/Edit Human View/Edit Mouse

Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the APC gene. [4] The APC protein is a negative regulator that controls beta-catenin concentrations and interacts with E-cadherin, which are involved in cell adhesion. Mutations in the APC gene may result in colorectal cancer and desmoid tumors. [5] [6]

APC is classified as a tumor suppressor gene. Tumor suppressor genes prevent the uncontrolled growth of cells that may result in cancerous tumors. The protein made by the APC gene plays a critical role in several cellular processes that determine whether a cell may develop into a tumor. The APC protein helps control how often a cell divides, how it attaches to other cells within a tissue, how the cell polarizes and the morphogenesis of the 3D structures, [7] or whether a cell moves within or away from tissue. This protein also helps ensure that the chromosome number in cells produced through cell division is correct. The APC protein accomplishes these tasks mainly through association with other proteins, especially those that are involved in cell attachment and signaling. The activity of one protein in particular, beta-catenin, is controlled by the APC protein (see: Wnt signaling pathway). Regulation of beta-catenin prevents genes that stimulate cell division from being turned on too often and prevents cell overgrowth.

The human APC gene is located on the long (q) arm of chromosome 5 in band q22.2 (5q22.2). The APC gene has been shown to contain an internal ribosome entry site. APC orthologs [8] have also been identified in all mammals for which complete genome data are available.

Structure

The full-length human protein comprises 2,843 amino acids with a (predicted) molecular mass of 311646 Da. Several N-terminal domains have been structurally elucidated in unique atomistic high-resolution complex structures. Most of the protein is predicted to be intrinsically disordered. It is not known if this large predicted unstructured region from amino acid 800 to 2843 persists in vivo or would form stabilised complexes – possibly with yet unidentified interacting proteins. [9] Recently, it has been experimentally confirmed that the mutation cluster region around the center of APC is intrinsically disordered in vitro. [10]

Role in cancer

The most common mutation in colon cancer is inactivation of APC. In absence of APC inactivating mutations, colon cancers commonly carry activating mutations in beta catenin or inactivating mutations in RNF43. [11] Mutations in APC can be inherited, or arise sporadically in the somatic cells, often as the result of mutations in other genes that result in the inability to repair mutations in the DNA. In order for cancer to develop, both alleles (copies of the APC gene) must be mutated. Mutations in APC or β-catenin must be followed by other mutations to become cancerous; however, in carriers of an APC-inactivating mutation, the risk of colorectal cancer by age 40 is almost 100%. [5]

Familial adenomatous polyposis (FAP) is caused by an inherited, inactivating mutation in the APC gene. [12] More than 800 mutations [ citation needed ] in the APC gene have been identified in families with classic and attenuated types of familial adenomatous polyposis. Most of these mutations cause the production of an APC protein that is abnormally short and presumably nonfunctional. This short protein cannot suppress the cellular overgrowth that leads to the formation of polyps, which can become cancerous. The most common mutation in familial adenomatous polyposis is a deletion of five bases in the APC gene. This mutation changes the sequence of amino acids in the resulting APC protein beginning at position 1309. Mutations in the APC gene have also been found to lead to the development of desmoid tumors in FAP patients. [6]

Another mutation is carried by approximately 6 percent[ citation needed ] of people of Ashkenazi (eastern and central European) Jewish heritage. This mutation results in the substitution of the amino acid lysine for isoleucine at position 1307 in the APC protein (also written as I1307K or Ile1307Lys). This change has been shown to be associated with an increased risk of colon cancer, [13] with moderate effect size. [14] APC I1307K has also been implicated as a risk factor for certain other cancers. [14]

Regulation of proliferation

The (Adenomatous Polyposis Coli) APC protein normally builds a "destruction complex" with glycogen synthase kinase 3-alpha and or beta (GSK-3α/β) and Axin via interactions with the 20 AA and SAMP repeats. [15] [16] [17] This complex is then able to bind β-catenins in the cytoplasm, that have dissociated from adherens contacts between cells. With the help of casein kinase 1 (CK1), which carries out an initial phosphorylation of β-catenin, GSK-3β is able to phosphorylate β-catenin a second time. This targets β-catenin for ubiquitination and degradation by cellular proteasomes. This prevents it from translocating into the nucleus, where it acts as a transcription factor for proliferation genes. [18] APC is also thought to be targeted to microtubules via the PDZ binding domain, stabilizing them. [19] The deactivation of the APC protein can take place after certain chain reactions in the cytoplasm are started, e.g. through the Wnt signals that destroy the conformation of the complex.[ citation needed ] In the nucleus it complexes with legless/BCL9, TCF, and Pygo.[ citation needed ]

The ability of APC to bind β-catenin has been classically considered to be an integral part of the protein's mechanistic function in the destruction complex, along with binding to Axin through the SAMP repeats. [20] These models have been substantiated by observations that common APC loss of function mutations in the mutation cluster region often remove several β-catenin binding sites and SAMP repeats. However, recent evidence from Yamulla and colleagues have directly tested those models and imply that APC's core mechanistic functions may not require direct binding to β-catenin, but necessitate interactions with Axin. [21] The researchers hypothesized that APC's many β-catenin binding sites increase the protein's efficiency at destroying β-catenin, yet are not absolutely necessary for the protein's mechanistic function. Further research is clearly necessary to elucidate the precise mechanistic function of APC in the destruction complex.

Mutations

Familial adenomatous polyposis of the intestine Familial Adenomatous Polyposis intestine.jpg
Familial adenomatous polyposis of the intestine

Mutations in APC often occur early on in cancers such as colon cancer. [9] Patients with familial adenomatous polyposis (FAP) have germline mutations, with 95% being nonsense/frameshift mutations leading to premature stop codons. 33% of mutations occur between amino acids 1061–1309. In somatic mutations, over 60% occur within a mutation cluster region (1286–1513), causing loss of axin-binding sites in all but one of the 20AA repeats. Mutations in APC lead to loss of β-catenin regulation, altered cell migration and chromosome instability. [11]

Neurological role

Rosenberg et al. found that APC directs cholinergic synapse assembly between neurons, a finding with implications for autonomic neuropathies, for Alzheimer's disease, for age-related hearing loss, and for some forms of epilepsy and schizophrenia. [22] (29)

Interactions

APC (gene) has been shown to interact with:

Overview of signal transduction pathways involved in apoptosis. Signal transduction pathways.svg
Overview of signal transduction pathways involved in apoptosis.

See also

Related Research Articles

Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.

<span class="mw-page-title-main">Gardner's syndrome</span> Medical condition

Gardner's syndrome is a subtype of familial adenomatous polyposis (FAP). Gardner syndrome is an autosomal dominant form of polyposis characterized by the presence of multiple polyps in the colon together with tumors outside the colon. The extracolonic tumors may include osteomas of the skull, thyroid cancer, epidermoid cysts, fibromas, as well as the occurrence of desmoid tumors in approximately 15% of affected individuals.

<span class="mw-page-title-main">Familial adenomatous polyposis</span> Medical condition

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine. While these polyps start out benign, malignant transformation into colon cancer occurs when they are left untreated. Three variants are known to exist, FAP and attenuated FAP are caused by APC gene defects on chromosome 5 while autosomal recessive FAP is caused by defects in the MUTYH gene on chromosome 1. Of the three, FAP itself is the most severe and most common; although for all three, the resulting colonic polyps and cancers are initially confined to the colon wall. Detection and removal before metastasis outside the colon can greatly reduce and in many cases eliminate the spread of cancer.

The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.

<span class="mw-page-title-main">Catenin</span>

Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells. The first two catenins that were identified became known as α-catenin and β-catenin. α-Catenin can bind to β-catenin and can also bind filamentous actin (F-actin). β-Catenin binds directly to the cytoplasmic tail of classical cadherins. Additional catenins such as γ-catenin and δ-catenin have been identified. The name "catenin" was originally selected because it was suspected that catenins might link cadherins to the cytoskeleton.

<span class="mw-page-title-main">Fundic gland polyposis</span> Medical condition

Fundic gland polyposis is a medical syndrome where the fundus and the body of the stomach develop many fundic gland polyps. The condition has been described both in patients with familial adenomatous polyposis (FAP) and attenuated variants (AFAP), and in patients in whom it occurs sporadically.

<span class="mw-page-title-main">Catenin beta-1</span> Mammalian protein found in Homo sapiens

Catenin beta-1, also known as β-catenin (beta-catenin), is a protein that in humans is encoded by the CTNNB1 gene.

<span class="mw-page-title-main">Plakoglobin</span> Mammalian protein found in Homo sapiens

Plakoglobin, also known as junction plakoglobin or gamma-catenin, is a protein that in humans is encoded by the JUP gene. Plakoglobin is a member of the catenin protein family and homologous to β-catenin. Plakoglobin is a cytoplasmic component of desmosomes and adherens junctions structures located within intercalated discs of cardiac muscle that function to anchor sarcomeres and join adjacent cells in cardiac muscle. Mutations in plakoglobin are associated with arrhythmogenic right ventricular dysplasia.

<span class="mw-page-title-main">CTNNBIP1</span> Protein-coding gene in the species Homo sapiens

Beta-catenin-interacting protein 1 is a protein that is encoded in humans by the CTNNBIP1 gene.

<span class="mw-page-title-main">AXIN1</span> Protein-coding gene in the species Homo sapiens

Axin-1 is a protein that in humans is encoded by the AXIN1 gene.

<span class="mw-page-title-main">Secreted frizzled-related protein 1</span> Protein-coding gene in the species Homo sapiens

Secreted frizzled-related protein 1, also known as SFRP1, is a protein which in humans is encoded by the SFRP1 gene.

<span class="mw-page-title-main">AXIN2</span> Protein-coding gene in the species Homo sapiens

Axin-2, also known as axin-like protein (Axil), axis inhibition protein 2 (AXIN2), or conductin, is a protein that in humans is encoded by the AXIN2 gene.

<span class="mw-page-title-main">Catenin alpha-1</span> Protein-coding gene in the species Homo sapiens

αE-catenin, also known as Catenin alpha-1 is a protein that in humans is encoded by the CTNNA1 gene. αE-catenin is highly expressed in cardiac muscle and localizes to adherens junctions at intercalated disc structures where it functions to mediate the anchorage of actin filaments to the sarcolemma. αE-catenin also plays a role in tumor metastasis and skin cell function.

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<span class="mw-page-title-main">Dishevelled</span> Family of proteins

Dishevelled (Dsh) is a family of proteins involved in canonical and non-canonical Wnt signalling pathways. Dsh is a cytoplasmic phosphoprotein that acts directly downstream of frizzled receptors. It takes its name from its initial discovery in flies, where a mutation in the dishevelled gene was observed to cause improper orientation of body and wing hairs. There are vertebrate homologs in zebrafish, Xenopus (Xdsh), mice and humans. Dsh relays complex Wnt signals in tissues and cells, in normal and abnormal contexts. It is thought to interact with the SPATS1 protein when regulating the Wnt Signalling pathway.

Naked cuticle 1 (NKD1) is a human gene that encodes the protein Nkd1, a member of the Naked cuticle (Nkd) family of proteins that regulate the Wnt signaling pathway. Insects typically have a single Nkd gene, whereas there are two Nkd genes, Nkd1 and Nkd2, in most vertebrates studied to date. Nkd1 binds to the Dishevelled (Dvl) family of proteins. Specific truncating NKD1 mutations identified in DNA mismatch repair deficient colon cancer that disrupt Nkd1/Dvl binding implicate these mutations as a cause of increased Wnt signaling in a subset of human colon cancers, the majority of which have increased Wnt signaling due to mutations the adenomatous polyposis coli (APC), AXIN2, or rarely the beta-catenin genes.

<span class="mw-page-title-main">Hereditary cancer syndrome</span> Inherited genetic condition that predisposes a person to cancer

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Kang-Yell Choi is a professor of biotechnology at Yonsei University, and has a joint appointment position as a CEO of CK Regeon Inc. in Seoul, Korea. He has been performing researches related to cellular signaling, especially for the Wnt/β-catenin pathway involving various pathophysiologies. Choi has been leading the Translational Research Center for Protein Function Control (TRCP), a Korean government supported drug development institute, as a director for 10 years. Choi has been carrying out R&D to develop agents controlling the Wnt/β-catenin signaling pathway. Choi's main interest is development of the agents to treat intractable diseases that suppress tissue regeneration system through overexpression of CXXC5 and subsequent suppression of the Wnt/β-catenin signaling.

<span class="mw-page-title-main">Apc, wnt signaling pathway regulator</span> Mammalian protein found in Homo sapiens

APC, WNT signaling pathway regulator is a protein that in humans is encoded by the APC gene.

Gardner fibroma (GF) is a benign fibroblastic tumor. GF tumors typically develop in the dermis and adjacent subcutaneous tissue lying just below the dermis. These tumors typically occur on the back, abdomen, and other superficial sites but in rare cases have been diagnoses in internal sites such as the retroperitoneum and around the large blood vessels in the upper thoracic cavity. The World Health Organization, 2020, classified Gardner fibroma as a benign tumor in the category of fibroblastic and myofibroblastic tumors.

References

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  37. ↑ Nakamura M, Zhou XZ, Lu KP (July 2001). "Critical role for the EB1 and APC interaction in the regulation of microtubule polymerization". Current Biology. 11 (13): 1062–1067. doi: 10.1016/S0960-9822(01)00297-4 . PMID   11470413. S2CID   14122895.
  38. ↑ Shibata T, Gotoh M, Ochiai A, Hirohashi S (August 1994). "Association of plakoglobin with APC, a tumor suppressor gene product, and its regulation by tyrosine phosphorylation". Biochemical and Biophysical Research Communications. 203 (1): 519–522. doi:10.1006/bbrc.1994.2213. PMID   8074697.
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