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Adenomatous polyposis coli

spinqualitylabelsall models Caption for this structure Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image is a multidomain tumour suppressor protein involved in the regulation of various cellular processes, such as cell adhesion, migration or proliferation[1]. It is expressed in plethora of organs and tissues, e. g. cerebral cortex, bronchi or the gastrointestinal tract[2]. Germline truncation mutations of APC result in familial adenomatous polyposis, a hereditary form of colon cancer[3]. Additionally, loss of the C-terminal portion of APC is detected in about 80 % of sporadic colon cancers[4]. Contents 1 The overall structure of APC 2 The physiological functions of APC and their implications for colorectal cancer onset and progression 2.1 Regulation of cell adhesion and migration 2.2 Regulation of cell proliferation through the Wnt pathway The overall structure of APC A schematic of the APC protein domain structure. MCR, mutation cluster region; SAMP, Axin-binding motif The APC protein, its primary sequence encompassing 2843 aminoacids[5], consists of multiple domains, which enable it to interact with diverse partners. At the N-terminus, an oligomerisation domain is found, enabling the APC protein to oligomerise. It is followed by so called pre-ARM region and seven armadillo repeats, which form a groove for binding of a guanine nucleotide exchange factor Asef[6]. The central part of APC contains three 15 aminoacid long repeats followed by seven 20 aminoacid long repeats[1]. These motifs serve as binding sites for β-catenin[7]. In between the 20 aminoacid repeats, three SAMP regions are dispersed, enabling the interaction with Axin[1]. At the C-terminus, a basic domain responsible for binding to microtubules as well as EB1 interaction domain are present[8][1]. Interestingly, majority of somatic mutations occurs in so called mutation cluster region (MCR) between codons 1286 and 1513[9]. The physiological functions of APC and their implications for colorectal cancer onset and progression Regulation of cell adhesion and migration The seven armadillo repeats (ARM) together with the so-called pre-ARM region adjoining them at the N-terminus are essential for binding the guanine nucleotide exchange factor Asef[6]. In the absence of APC, Asef adopts an autoinhibited conformation, which prevents it from interaction with the small GTPase Cdc42[10]. Upon APC binding, the autoinhibited conformation of Asef is disrupted and the binding site for Cdc42 is made accessible[6]. Interaction with Asef leads to the exchange of GDP for GTP in the Cdc42 protein, which in turn modulates adherent junctions and contributes to enhanced cell motility[11][10][6]. In colorectal cancers, the truncated version of APC with preserved pre-ARM and ARM domains constitutively activates Asef and hence Cdc42[12]. This leads to extracellular matrix remodelling and promotion of adhesion-independent growth and cell migration[13]. Interestingly, APC takes part in strengthening the adherent junctions through the regulation of cellular distribution of E-cadherin and β-catenin. Full-length APC leads to increased levels of E-cadherin at the plasma membrane and decreases the pool of nuclear β-catenin in favour of the cytosolic one, enabling adherent junctions to be formed[14]. On the other hand, the truncated form of APC lacking the β-catenin interaction motifs is unable of such actions[11]. Regulation of cell proliferation through the Wnt pathway APC controls cell proliferation as a negative regulator of the Wnt signalling pathway. Together with Axin, GSK3-β, CK1, PP2A and SCFβ-TRCP E3-ubiquitin ligase, APC forms so-called destruction complex, whose role is to promote the degradation of β-catenin[15][16][17]. APC binds Axin through the SAMP regions in APC central part, stabilises it and enables its oligomerisation[18]. Moreover, it has been proposed that APC supports the disociation of phosphorylated (=marked for degradation) β-catenin from the destruction complex[18] and that it is also essential for the movement of the destruction complex towards the plasma membrane[17]. However, degradation of β-catenin is not the only way employed by APC to antagonise the Wnt signalling. β-catenin binding motifs in the central part of APC compete with other interaction partners of β-catenin, such as the transcription factor TCF, thus preventing the expression of pro-proliferative factors (cyclin D, c-myc)[19][20][21][22][23]. Additionally, APC was observed to facilitate the export of β-catenin from the nucleus, hence delivering it out of reach of its target transcription factors[24][25]. Truncated APC defective in β-catenin binding can not effectively control the Wnt pathway signalling either by promoting β-catenin degradation or by preventing it from interacting with transcription factors, which might lead to overactivation of cyclin D or c-myc expression and hence excessive proliferation[19][20][25][18]. However, the first β-catenin binding repeat is often preserved in truncated APC mutants in colorectal carcinomas, which has brought forth the hypothesis that preserving some level of β-catenin downregulation is necessary to balance the potentionally harmful outcomes of constitutive β-catenin activation[26][27][28]

References

1. ↑ ^{1.0 1.1 1.2 1.3} Zhang, L. and Shay, J. W. (2017) ‘Multiple Roles of APC and its Therapeutic Implications in Colorectal Cancer.’, Journal of the National Cancer Institute, 109(8). doi: 10.1093/jnci/djw332.
2. ↑ https://www.proteinatlas.org/ENSG00000134982-APC/tissue
3. ↑ Ficari, F. et al. (2000) ‘APC gene mutations and colorectal adenomatosis in familial adenomatous polyposis’, British Journal of Cancer. Churchill Livingstone, 82(2), pp. 348–353. doi: 10.1054/bjoc.1999.0925.
4. ↑ Rowan, A. J. et al. (2000) ‘APC mutations in sporadic colorectal tumors: A mutational “hotspot” and interdependence of the “two hits”’, Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences, 97(7), pp. 3352–3357. doi: 10.1073/pnas.97.7.3352.
5. ↑ https://www.uniprot.org/uniprot/P25054
6. ↑ ^{6.0 6.1 6.2 6.3} Zhang, Z. et al. (2012) ‘Structural basis for the recognition of Asef by adenomatous polyposis coli’, Cell Research. Nature Publishing Group, 22(2), pp. 372–386. doi: 10.1038/cr.2011.119.
7. ↑ Hou, F. et al. (2011) ‘MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response.’, Cell. Elsevier, 146(3), pp. 448–61. doi: 10.1016/j.cell.2011.06.041.
8. ↑ Su, L. K. et al. (1995) ‘APC Binds to the Novel Protein EB’, Cancer Research, 55(14), pp. 2972–2977.
9. ↑ Miyoshi, Y. et al. (1992) Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene | Human Molecular Genetics | Oxford Academic, Human Molecular Genetics, Vol. 1, No. 4 229-233. Available at: https://academic.oup.com/hmg/article/1/4/229/730109 (Accessed: 22 April 2020).)
10. ↑ ^{10.0 10.1} Mitin, N. et al. (2007) ‘Release of autoinhibition of ASEF by APC leads to CDC42 activation and tumor suppression’, Nature Structural and Molecular Biology, 14(9), pp. 814–823. doi: 10.1038/nsmb1290.
11. ↑ ^{11.0 11.1} Kawasaki, Y., Sato, R. and Akiyama, T. (2003) ‘Mutated APC and Asef are involved in the migration of colorectal tumour cells’, Nature Cell Biology, 5(3), pp. 211–215. doi: 10.1038/ncb937.
12. ↑ Kawasaki, Y. et al. (2010) ‘The adenomatous polyposis coli-associated guanine nucleotide exchange factor Asef is involved in angiogenesis’, Journal of Biological Chemistry, 285(2), pp. 1199–1207. doi: 10.1074/jbc.M109.040691.
13. ↑ Kawasaki, Y. et al. (2009) ‘The adenomatous polyposis coli-associated exchange factors Asef and Asef2 are required for adenoma formation in ApcMin/+mice’, EMBO Reports, 10(12), pp. 1355–1362. doi: 10.1038/embor.2009.233.
14. ↑ Faux, M. C. et al. (2004) ‘Restoration of full-length adenomatous polyposis coli (APC) protein in a colon cancer cell line enhances cell adhesion’, Journal of Cell Science, 117(3), pp. 427–439. doi: 10.1242/jcs.00862.
15. ↑ Aberle, H. et al. (1997) ‘beta-catenin is a target for the ubiquitin-proteasome pathway.’, The EMBO journal, 16(13), pp. 3797–804. doi: 10.1093/emboj/16.13.3797.
16. ↑ Liu, C. et al. (2002) ‘Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism’, Cell. Cell Press, 108(6), pp. 837–847. doi: 10.1016/S0092-8674(02)00685-2.
17. ↑ ^{17.0 17.1} Parker, T. W. and Neufeld, K. L. (2020) ‘APC controls Wnt-induced β-catenin destruction complex recruitment in human colonocytes’, Scientific Reports. Nature Research, 10(1). doi: 10.1038/s41598-020-59899-z.
18. ↑ ^{18.0 18.1 18.2} Pronobis, M. I., Rusan, N. M. and Peifer, M. (2015) ‘A novel GSK3-regulated APC:Axin interaction regulates Wnt signaling by driving a catalytic cycle of efficient βcatenin destruction.’, eLife. eLife Sciences Publications Ltd, 4(September 2015), p. e08022. doi: 10.7554/eLife.08022.
19. ↑ ^{19.0 19.1} He, T. C. et al. (1998) ‘Identification of c-MYC as a target of the APC pathway’, Science, 281(5382), pp. 1509–1512. doi: 10.1126/science.281.5382.1509.
20. ↑ ^{20.0 20.1} Tetsu, O. and McCormick, F. (1999) ‘β-catenin regulates expression of cyclin D1 in colon carcinoma cells’, Nature, 398(6726), pp. 422–426. doi: 10.1038/18884.
21. ↑ Neufeld, K. L. et al. (2000) ‘APC-mediated downregulation of beta-catenin activity involves nuclear sequestration and nuclear export.’, EMBO reports, 1(6), pp. 519–23. doi: 10.1093/embo-reports/kvd117.
22. ↑ Hamada, F. and Bienz, M. (2004) ‘The APC tumor suppressor binds to C-terminal binding protein to divert nuclear β-catenin from TCF’, Developmental Cell, 7(5), pp. 677–685. doi: 10.1016/j.devcel.2004.08.022.
23. ↑ Sierra, J. et al. (2006) ‘The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes.’, Genes & development, 20(5), pp. 586–600. doi: 10.1101/gad.1385806.
24. ↑ Henderson, B. R. (2000) ‘Nuclear-cytoplasmic shuttling of APC regulates β-catenin subcellular localization and turnover’, Nature Cell Biology, 2(9), pp. 653–660. doi: 10.1038/35023605.
25. ↑ ^{25.0 25.1} Rosin-Arbesfeld, R., Townsley, F. and Blenz, M. (2000) ‘The APC tumour suppressor has a nuclear export function’, Nature, 406(6799), pp. 1009–1012. doi: 10.1038/35023016.
26. ↑ Albuquerque, C. (2002) ‘The “just-right” signaling model: APC somatic mutations are selected based on a specific level of activation of the beta-catenin signaling cascade’, Human Molecular Genetics. Oxford University Press (OUP), 11(13), pp. 1549–1560. doi: 10.1093/hmg/11.13.1549.
27. ↑ Schneikert, J., Grohmann, A. and Behrens, J. (2007) ‘Truncated APC regulates the transcriptional activity of beta-catenin in a cell cycle dependent manner.’, Human molecular genetics, 16(2), pp. 199–209. doi: 10.1093/hmg/ddl464.
28. ↑ .

    Contents 1 Regulation of cell division 2 Gain of function APC mutants 3 Structural insights into APC interactions 3.1 Activation of Asef

    Regulation of cell division

    Gain of function APC mutants

    Structural insights into APC interactions

    Activation of Asef

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