| Structural highlights
Disease
[APC_HUMAN] 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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] 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.[11] [12] 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).[13] [14] [15] 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.[16] [17] [18] 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.[19] [20] Defects in APC are a cause of hepatocellular carcinoma (HCC) [MIM:114550]. This defect includes also the disease entity termed hepatoblastoma.[21] [22] [AMER1_HUMAN] Osteopathia striata - cranial sclerosis. The disease is caused by mutations affecting the gene represented in this entry.
Function
[APC_HUMAN] 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.[23] [24] [25] [26] [27] [AMER1_HUMAN] Regulator of the canonical Wnt signaling pathway. Acts by specifically binding phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), translocating to the cell membrane and interacting with key regulators of the canonical Wnt signaling pathway, such as components of the beta-catenin destruction complex. Acts both as a positive and negative regulator of the Wnt signaling pathway, depending on the context: acts as a positive regulator by promoting LRP6 phosphorylation. Also acts as a negative regulator by acting as a scaffold protein for the beta-catenin destruction complex and promoting stabilization of Axin at the cell membrane. Promotes CTNNB1 ubiquitination and degradation. Involved in kidney development.[28] [29] [30] [31] [32]
Publication Abstract from PubMed
The tumor suppressor APC employs its conserved armadillo repeat (ARM) domain to recognize many of its binding partners, including Amer1/WTX, which is mutated in Wilms' tumor and bone overgrowth syndrome. The APC-Amer1 complex has important roles in regulating Wnt signaling and cell adhesion. Three sites A1, A2, and A3 of Amer1 have been reported to mediate its interaction with APC-ARM. In this study, crystal structures of APC-ARM in complexes with Amer1-A1, -A2, and -A4, which is newly identified in this work, were determined. Combined with our GST pull-down, yeast two-hybrid, and isothermal titration calorimetry (ITC) assay results using mutants of APC and Amer1 interface residues, our structures demonstrate that Amer1-A1, -A2, and -A4, as well as other APC-binding proteins such as Asef and Sam68, all employ a common recognition pattern to associate with APC-ARM. In contrast, Amer1-A3 binds to the C-terminal side of APC-ARM through a bipartite interaction mode. Composite mutations on either APC or Amer1 disrupting all four interfaces abrogated their association in cultured cells and impaired the membrane recruitment of APC by Amer1. Our study thus comprehensively elucidated the recognition mechanism between APC and Amer1, and revealed a consensus recognition sequence employed by various APC-ARM binding partners.
Structures of the APC-ARM domain in complexes with discrete Amer1/WTX fragments reveal that it uses a consensus mode to recognize its binding partners.,Zhang Z, Akyildiz S, Xiao Y, Gai Z, An Y, Behrens J, Wu G Cell Discov. 2015 Jul 14;1:15016. doi: 10.1038/celldisc.2015.16. eCollection, 2015. PMID:27462415[33]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Eccles DM, van der Luijt R, Breukel C, Bullman H, Bunyan D, Fisher A, Barber J, du Boulay C, Primrose J, Burn J, Fodde R. Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet. 1996 Dec;59(6):1193-201. PMID:8940264
- ↑ Couture J, Mitri A, Lagace R, Smits R, Berk T, Bouchard HL, Fodde R, Alman B, Bapat B. A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. Clin Genet. 2000 Mar;57(3):205-12. PMID:10782927
- ↑ Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, Koyama K, Utsunomiya J, Baba S, Hedge P. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science. 1991 Aug 9;253(5020):665-9. PMID:1651563
- ↑ Miyoshi Y, Nagase H, Ando H, Horii A, Ichii S, Nakatsuru S, Aoki T, Miki Y, Mori T, Nakamura Y. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet. 1992 Jul;1(4):229-33. PMID:1338904
- ↑ Nakatsuru S, Yanagisawa A, Ichii S, Tahara E, Kato Y, Nakamura Y, Horii A. Somatic mutation of the APC gene in gastric cancer: frequent mutations in very well differentiated adenocarcinoma and signet-ring cell carcinoma. Hum Mol Genet. 1992 Nov;1(8):559-63. PMID:1338691
- ↑ Nagase H, Miyoshi Y, Horii A, Aoki T, Petersen GM, Vogelstein B, Maher E, Ogawa M, Maruyama M, Utsunomiya J, et al.. Screening for germ-line mutations in familial adenomatous polyposis patients: 61 new patients and a summary of 150 unrelated patients. Hum Mutat. 1992;1(6):467-73. PMID:1338764 doi:http://dx.doi.org/10.1002/humu.1380010603
- ↑ Dobbie Z, Spycher M, Hurliman R, Ammann R, Ammann T, Roth J, Muller A, Muller H, Scott RJ. Mutational analysis of the first 14 exons of the adenomatous polyposis coli (APC) gene. Eur J Cancer. 1994;30A(11):1709-13. PMID:7833149
- ↑ Stella A, Montera M, Resta N, Marchese C, Susca F, Gentile M, Romio L, Pilia S, Prete F, Mareni C, et al.. Four novel mutations of the APC (adenomatous polyposis coli) gene in FAP patients. Hum Mol Genet. 1994 Sep;3(9):1687-8. PMID:7833931
- ↑ van der Luijt RB, Khan PM, Vasen HF, Tops CM, van Leeuwen-Cornelisse IS, Wijnen JT, van der Klift HM, Plug RJ, Griffioen G, Fodde R. Molecular analysis of the APC gene in 105 Dutch kindreds with familial adenomatous polyposis: 67 germline mutations identified by DGGE, PTT, and southern analysis. Hum Mutat. 1997;9(1):7-16. PMID:8990002 doi:<7::AID-HUMU2>3.0.CO;2-8 10.1002/(SICI)1098-1004(1997)9:1<7::AID-HUMU2>3.0.CO;2-8
- ↑ Lamlum H, Ilyas M, Rowan A, Clark S, Johnson V, Bell J, Frayling I, Efstathiou J, Pack K, Payne S, Roylance R, Gorman P, Sheer D, Neale K, Phillips R, Talbot I, Bodmer W, Tomlinson I. The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: a new facet to Knudson's 'two-hit' hypothesis. Nat Med. 1999 Sep;5(9):1071-5. PMID:10470088 doi:10.1038/12511
- ↑ Eccles DM, van der Luijt R, Breukel C, Bullman H, Bunyan D, Fisher A, Barber J, du Boulay C, Primrose J, Burn J, Fodde R. Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet. 1996 Dec;59(6):1193-201. PMID:8940264
- ↑ Couture J, Mitri A, Lagace R, Smits R, Berk T, Bouchard HL, Fodde R, Alman B, Bapat B. A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. Clin Genet. 2000 Mar;57(3):205-12. PMID:10782927
- ↑ Eccles DM, van der Luijt R, Breukel C, Bullman H, Bunyan D, Fisher A, Barber J, du Boulay C, Primrose J, Burn J, Fodde R. Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet. 1996 Dec;59(6):1193-201. PMID:8940264
- ↑ Couture J, Mitri A, Lagace R, Smits R, Berk T, Bouchard HL, Fodde R, Alman B, Bapat B. A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. Clin Genet. 2000 Mar;57(3):205-12. PMID:10782927
- ↑ Huang H, Mahler-Araujo BM, Sankila A, Chimelli L, Yonekawa Y, Kleihues P, Ohgaki H. APC mutations in sporadic medulloblastomas. Am J Pathol. 2000 Feb;156(2):433-7. PMID:10666372
- ↑ Eccles DM, van der Luijt R, Breukel C, Bullman H, Bunyan D, Fisher A, Barber J, du Boulay C, Primrose J, Burn J, Fodde R. Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet. 1996 Dec;59(6):1193-201. PMID:8940264
- ↑ Couture J, Mitri A, Lagace R, Smits R, Berk T, Bouchard HL, Fodde R, Alman B, Bapat B. A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. Clin Genet. 2000 Mar;57(3):205-12. PMID:10782927
- ↑ Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B, et al.. The molecular basis of Turcot's syndrome. N Engl J Med. 1995 Mar 30;332(13):839-47. PMID:7661930
- ↑ Eccles DM, van der Luijt R, Breukel C, Bullman H, Bunyan D, Fisher A, Barber J, du Boulay C, Primrose J, Burn J, Fodde R. Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet. 1996 Dec;59(6):1193-201. PMID:8940264
- ↑ Couture J, Mitri A, Lagace R, Smits R, Berk T, Bouchard HL, Fodde R, Alman B, Bapat B. A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. Clin Genet. 2000 Mar;57(3):205-12. PMID:10782927
- ↑ Eccles DM, van der Luijt R, Breukel C, Bullman H, Bunyan D, Fisher A, Barber J, du Boulay C, Primrose J, Burn J, Fodde R. Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet. 1996 Dec;59(6):1193-201. PMID:8940264
- ↑ Couture J, Mitri A, Lagace R, Smits R, Berk T, Bouchard HL, Fodde R, Alman B, Bapat B. A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. Clin Genet. 2000 Mar;57(3):205-12. PMID:10782927
- ↑ Kawasaki Y, Senda T, Ishidate T, Koyama R, Morishita T, Iwayama Y, Higuchi O, Akiyama T. Asef, a link between the tumor suppressor APC and G-protein signaling. Science. 2000 Aug 18;289(5482):1194-7. PMID:10947987
- ↑ Kawasaki Y, Sagara M, Shibata Y, Shirouzu M, Yokoyama S, Akiyama T. Identification and characterization of Asef2, a guanine-nucleotide exchange factor specific for Rac1 and Cdc42. Oncogene. 2007 Dec 6;26(55):7620-267. Epub 2007 Jun 18. PMID:17599059 doi:10.1038/sj.onc.1210574
- ↑ Kawasaki Y, Tsuji S, Muroya K, Furukawa S, Shibata Y, Okuno M, Ohwada S, Akiyama T. The adenomatous polyposis coli-associated exchange factors Asef and Asef2 are required for adenoma formation in Apc(Min/+)mice. EMBO Rep. 2009 Dec;10(12):1355-62. doi: 10.1038/embor.2009.233. Epub 2009 Nov 6. PMID:19893577 doi:10.1038/embor.2009.233
- ↑ Sagara M, Kawasaki Y, Iemura SI, Natsume T, Takai Y, Akiyama T. Asef2 and Neurabin2 cooperatively regulate actin cytoskeletal organization and are involved in HGF-induced cell migration. Oncogene. 2009 Mar 12;28(10):1357-65. doi: 10.1038/onc.2008.478. Epub 2009 Jan, 19. PMID:19151759 doi:10.1038/onc.2008.478
- ↑ Zaoui K, Benseddik K, Daou P, Salaun D, Badache A. ErbB2 receptor controls microtubule capture by recruiting ACF7 to the plasma membrane of migrating cells. Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18517-22. doi:, 10.1073/pnas.1000975107. Epub 2010 Oct 11. PMID:20937854 doi:10.1073/pnas.1000975107
- ↑ Major MB, Camp ND, Berndt JD, Yi X, Goldenberg SJ, Hubbert C, Biechele TL, Gingras AC, Zheng N, Maccoss MJ, Angers S, Moon RT. Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling. Science. 2007 May 18;316(5827):1043-6. PMID:17510365 doi:http://dx.doi.org/10.1126/science/1141515
- ↑ Grohmann A, Tanneberger K, Alzner A, Schneikert J, Behrens J. AMER1 regulates the distribution of the tumor suppressor APC between microtubules and the plasma membrane. J Cell Sci. 2007 Nov 1;120(Pt 21):3738-47. Epub 2007 Oct 9. PMID:17925383 doi:http://dx.doi.org/10.1242/jcs.011320
- ↑ Rivera MN, Kim WJ, Wells J, Stone A, Burger A, Coffman EJ, Zhang J, Haber DA. The tumor suppressor WTX shuttles to the nucleus and modulates WT1 activity. Proc Natl Acad Sci U S A. 2009 May 19;106(20):8338-43. doi:, 10.1073/pnas.0811349106. Epub 2009 May 4. PMID:19416806 doi:10.1073/pnas.0811349106
- ↑ Tanneberger K, Pfister AS, Brauburger K, Schneikert J, Hadjihannas MV, Kriz V, Schulte G, Bryja V, Behrens J. Amer1/WTX couples Wnt-induced formation of PtdIns(4,5)P2 to LRP6 phosphorylation. EMBO J. 2011 Apr 20;30(8):1433-43. doi: 10.1038/emboj.2011.28. Epub 2011 Feb 8. PMID:21304492 doi:http://dx.doi.org/10.1038/emboj.2011.28
- ↑ Tanneberger K, Pfister AS, Kriz V, Bryja V, Schambony A, Behrens J. Structural and functional characterization of the Wnt inhibitor APC membrane recruitment 1 (Amer1). J Biol Chem. 2011 Jun 3;286(22):19204-14. doi: 10.1074/jbc.M111.224881. Epub 2011, Apr 15. PMID:21498506 doi:http://dx.doi.org/10.1074/jbc.M111.224881
- ↑ Zhang Z, Akyildiz S, Xiao Y, Gai Z, An Y, Behrens J, Wu G. Structures of the APC-ARM domain in complexes with discrete Amer1/WTX fragments reveal that it uses a consensus mode to recognize its binding partners. Cell Discov. 2015 Jul 14;1:15016. doi: 10.1038/celldisc.2015.16. eCollection, 2015. PMID:27462415 doi:http://dx.doi.org/10.1038/celldisc.2015.16
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