Abstract
The tumour suppressor adenomatous polyposis coli (APC) is mutated in sporadic and familial colorectal tumours. APC binds to β-catenin, a key component of the Wnt signalling pathway, and induces its degradation. In addition to this role, there is increasing evidence for additional roles of APC, including the organization of cytoskeletal networks. APC interacts with microtubules and accumulates at their plus ends in membrane protrusions. Also, it has been reported that APC is associated with the plasma membrane in an actin-dependent manner. Moreover, APC interacts with IQGAP1, an effector of Rac1 and Cdc42, and APC-stimulated guanine nucleotide exchange factor (Asef), a Rac1-specific guanine nucleotide exchange factor (GEF). IQGAP1 mediates association of APC with cortical actin in the leading edge of migrating cell and both proteins are required for cell polarization and directional migration. APC interacts with Asef and stimulates its activity, thereby regulating the actin cytoskeletal network, cell morphology, adhesion and migration. Truncated mutant APCs present in colorectal tumour cells activate Asef constitutively and contribute to their aberrant migratory properties, which may be important for adenoma formation as well as tumour progression to invasive malignancy.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Askham JM, Moncur P, Markham AF, Morrison EE . (2000). Regulation and function of the interaction between the APC tumour suppressor protein and EB1. Oncogene 19: 1950–1958.
Bashour A-M, Fullerton AT, Hart MJ, Bloom GS . (1997). IQGAP1, a Rac- and Cdc42-binding protein, directly binds and cross-links microfilaments. J Cell Biol 37: 1555–1566.
Bienz M . (2002). The subcellular destinations of APC proteins. Nat Rev Mol Cell Biol 3: 328–338.
Bienz M, Clevers H . (2000). Linking colorectal cancer to Wnt signaling. Cell 103: 311–320.
Bienz M, Hamada F . (2004). Adenomatous polyposis coli proteins and cell adhesion. Curr Opin Cell Biol 16: 528–535.
Braga VMM, Betson M, Li X, Lamarche-Vane N . (2000). Activation of the small GTPase Rac is sufficient to disrupt cadherin-dependent cell–cell adhesion in normal human keratinocytes. Mol Biol Cell 11: 3703–3721.
Briggs MW, Sacks DB . (2003). IQGAP1 as signal integrator: Ca2+, calmodulin, Cdc42 and the cytoskeleton. FEBS Lett 542: 7–11.
Brocardo M, Nathke IS, Henderson BR . (2005). Redefining the subcellular location and transport of APC: new insights using a panel of antibodies. EMBO Rep 6: 184–190.
Cadigan KM, Nusse R . (1997). Wnt signaling: a common theme in animal development. Genes Dev 11: 3052–3286.
Etienne-Manneville S, Hall A . (2003). Cdc42 regulates GSK-3β and adenomatous polyposis coli to control cell polarity. Nature 421: 753–756.
Etienne-Manneville S, Manneville J-B, Nicholls S, Ferenczi MA, Hall A . (2005). Cdc42 and Par6-PKCzeta regulate the spatially localized association of Dlg1 and APC to control cell polarization. J Cell Biol 170: 895–901.
Faux MC, Ross JL, Meeker C, Johns T, Ji H, Simpson RJ et al. (2004). Restoration of full-length adenomatous polyposis coli (APC) protein in a colon cancer cell line enhances cell adhesion. J Cell Sci 117: 427–439.
Fodde R, Smits R, Clevers H . (2001). APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer 1: 55–67.
Fukuta M, Watanabe T, Noritake J, Nakagawa M, Yamaga M, Kuroda S et al. (2002). Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170. Cell 109: 873–885.
Hordijk PL, ten Klooster JP, van der Kammen RA, Michiels F, Oomen LC, Collard JG . (1997). Inhibition of invasion of epithelial cells by Tiam1-Rac signaling. Science 278: 1464–1466.
Jimbo T, Kawasaki Y, Koyama R, Sato R, Takada S, Haraguchi K et al. (2002). Identification of a link between the tumour suppressor APC and the kinesin superfamily. Nat Cell Biol 4: 323–327.
Kawasaki Y, Sato R, Akiyama T . (2003). Mutated APC and Asef are involved in the migration of colorectal tumour cells. Nat Cell Biol 5: 211–215.
Kawasaki Y, Senda T, Ishidate T, Koyama R, Morishita T, Iwayama Y et al. (2000). Asef, a link between the tumor suppressor APC and G-protein signaling. Science 289: 1194–1197.
Keely PJ, Westwick JK, Whitehead IP, Der CJ, Parise LV . (1997). Cdc42 and Rac1 induce integrin-mediated cell motility and invasiveness through PI(3)K. Nature 390: 632–636.
Langford KJ, Askham JM, Lee T, Adams M, Morrison EE . (2006). Examination of actin and microtubule dependent APC localisations in living mammalian cells. BMC Cell Biol 7: 3.
Mateer SC, Wang N, Bloom GS . (2003). IQGAPs: integrators of the cytoskeleton, cell adhesion machinery, and signaling networks. Cell Motil Cytoskeleton 55: 147–155.
Matsumine A, Ogai A, Senda T, Okumura N, Satoh K, Baeg G-H et al. (1996). Binding of APC to the human homolog of the Drosophila discs large tumor suppressor protein. Science 272: 1020–1023.
McCartney BM, Peifer M . (2000). Teaching tumour suppressors new tricks. Nat Cell Biol 2: E58–E60.
McCartney BM, Price MH, Webb RL, Hayden MA, Holot LM, Zhou M et al. (2006). Testing hypotheses for the functions of APC family proteins using null and truncation alleles in Drosophila. Development 133: 2407–2418.
Miki H, Okada Y, Hirokawa N . (2005). Analysis of the kinesin superfamily: insights into structure and function. Trends Cell Biol 15: 467–476.
Mimori-Kiyosue Y, Shiina N, Tsukita S . (2000a). The dynamic behavior of the APC-binding protein EB1 on the distal ends of microtubules. Curr Biol 10: 865–868.
Mimori-Kiyosue Y, Shiina N, Tsukita S . (2000b). Adenomatous polyposis coli (APC) protein moves along microtubules and concentrates at their growing ends in epithelial cells. J Cell Biol 148: 505–518.
Miyashiro I, Senda T, Matsumine A, Baeg G-H, Kuroda T, Shimano T et al. (1995). Subcellular localization of the APC protein: immunoelectron microscopic study of the association of the APC protein with catenin. Oncogene 11: 89–96.
Munemitsu S, Souza B, Muller O, Albert I, Rubinfeld B, Polakis P . (1994). The APC gene product associates with microtubules in vivo and promotes their assembly in vitro. Cancer Res 54: 3676–3681.
Nathke IS, Adams CL, Polakis P, Sellin JH, Nelson WJ . (1996). The adenomatous polyposis coli tumor suppressor protein localizes to plasma membrane sites involved in active cell migration. J Cell Biol 134: 165–179.
Oshima H, Oshima M, Kobayashi M, Tsutsumi M, Taketo MM . (1997). Morphological and molecular processes of polyp formation in Apc (delta716) knockout mice. Cancer Res 57: 1644–1649.
Polakis P . (2000). Wnt signaling and cancer. Genes Dev 14: 1837–1851.
Reilein WJ, Nelson WJ . (2005). APC is a component of an organizing template for cortical microtubule networks. Nat Cell Biol 7: 463–473.
Rosin-Arbesfeld R, Ihrke G, Bienz M . (2001). Actin-dependent membrane association of the APC tumour suppressor in polarized mammalian epithelial cells. EMBO J 20: 5929–5939.
Samowitz WS, Powers MD, Spirio LN, Nollet F, van Roy F, Slattery ML . (1999). Beta-catenin mutations are more frequent in small colorectal adenomas than in larger adenomas and invasive carcinomas. Cancer Res 59: 1442–1444.
Sander EE, van Delft S, ten Klooster JP, Reid T, van der Kammen RA, Michiels F et al. (1998). Matrix-dependent Tiam1/Rac signaling in epithelial cells promotes either cell–cell adhesion or cell migration and is regulated by phosphatidylinositol 3-kinase. J Cell Biol 143: 1385–1398.
Sansom OJ, Reed KR, Hayes AJ, Ireland H, Brinkmann H, Newton IP et al. (2004). Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev 18: 1385–1390.
Scholey JM . (1996). Kinesin-II, a membrane traffic motor in axons, axonemes, and spindles. J Cell Biol 133: 1–4.
Sharma M, Leung L, Bocardo M, Henderson J, Flegg C, Henderson BR . (2006). Membrane localization of adenomatous polyposis coli protein at cellular protrusions: targeting sequences and regulation by β-catenin. J Biol Chem 281: 17140–17149.
Su LK, Burrell M, Hill DE, Gyrus J, Brent R, Wiltshire R et al. (1995). APC binds to the novel protein EB1. Cancer Res 55: 2972–2977.
Takaishi K, Sasaki T, Kotani H, Nishioka H, Takai Y . (1997). Regulation of cell–cell adhesion by Rac and Rho small G proteins in MDCK cells. J Cell Biol 139: 1047–1059.
Watanabe T, Wang S, Noritake J, Sato K, Fukuta M, Takefuji M et al. (2005). Interaction with IQGAP1 links APC to Rac1, Cdc42, and actin filaments during cell polarization and migration. Dev Cell 7: 871–883.
Wen Y, Eng CH, Schmoranzer J, Cabrera-Poch N, Morris EJ, Chen M et al. (2004). EB1 and APC bind to mDia to stabilize microtubules downstream of Rho and promote cell migration. Nat Cell Biol 6: 820–830.
Wong MH, Hermiston ML, Syder AJ, Gordon JI . (1996). Forced expression of the tumor suppressor adenomatous polyposis coli protein induces disordered cell migration in the intestinal epithelium. Proc Natl Acad Sci USA 93: 9588–9593.
Zumbrunn J, Kinoshita K, Hyman AA, Nathke IS . (2001). Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3 beta phosphorylation. Curr Biol 11: 44–49.
Acknowledgements
We thank M Bienz for valuable comments on this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Akiyama, T., Kawasaki, Y. Wnt signalling and the actin cytoskeleton. Oncogene 25, 7538–7544 (2006). https://doi.org/10.1038/sj.onc.1210063
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1210063
Keywords
This article is cited by
-
Discovering biomarkers for hormone-dependent tumors: in silico study on signaling pathways implicated in cell cycle and cytoskeleton regulation
Molecular Genetics and Genomics (2022)
-
Peptidomimetic inhibitors of APC–Asef interaction block colorectal cancer migration
Nature Chemical Biology (2017)
-
Overexpression of Suprabasin is Associated with Proliferation and Tumorigenicity of Esophageal Squamous Cell Carcinoma
Scientific Reports (2016)
-
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 Discovery (2015)
-
UBE2Q1 expression in human colorectal tumors and cell lines
Molecular Biology Reports (2013)