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Identification of a link between the tumour suppressor APC and the kinesin superfamily

Abstract

The tumour suppressor gene adenomatous polyposis coli (APC) is mutated in sporadic and familial colorectal tumours1,2,3. APC is involved in the proteasome-mediated degradation of β-catenin, through its interaction with β-catenin, GSK-3β and Axin4,5. APC also interacts with the microtubule cytoskeleton6,7,8 and has been localized to clusters near the distal ends of microtubules at the edges of migrating epithelial cells9. Moreover, in Xenopus laevis epithelial cells, APC has been shown to move along microtubules and accumulate at their growing plus ends10. However, the mechanism of APC accumulation and the nature of these APC clusters remain unknown. We show here that APC interacts with the kinesin superfamily (KIF) 3A–KIF3B proteins, microtubule plus-end-directed motor proteins, through an association with the kinesin superfamily-associated protein 3 (KAP3). The interaction of APC with KAP3 was required for its accumulation in clusters, and mutant APCs derived from cancer cells were unable to accumulate efficiently in clusters. These results suggest that APC and β-catenin are transported along microtubules by KAP3–KIF3A–KIF3B, accumulate in the tips of membrane protrusions, and may thus regulate cell migration.

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Figure 1: Association of APC with KAP3.
Figure 2: Colocalization of APC, KAP3 and β-catenin to the tips of membrane protrusions in MDCK cells.
Figure 3: Effects of KAP3-ΔArm5 on APC cluster formation.
Figure 4: APC in colorectal tumour cells.

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Acknowledgements

We thank M. Lamphier for reading the manuscript, and T. Okabe, O. Higuchi, S. Adachi and T. Nakamura for their comments. We also thank T. Shibutani, K. Nawa, M. Hasumura and C. Imada for technical assistance, and K. Satoh, M. Kurimoto and T. Noda for the anti-APC monoclonal antibody. This work was supported by Grants-in-Aid for Scientific Research on Priority Areas, the Organization for Pharmaceutical Safety and Research and the Daiichi Pharmaceutical Company, Ltd.

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Correspondence to Tetsu Akiyama.

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Jimbo, T., Kawasaki, Y., Koyama, R. et al. Identification of a link between the tumour suppressor APC and the kinesin superfamily. Nat Cell Biol 4, 323–327 (2002). https://doi.org/10.1038/ncb779

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