Identification of a link between the tumour suppressor APC and the kinesin superfamily.
The tumour suppressor gene adenomatous polyposis coli (APC) is mutated in sporadic and familial colorectal tumours. APC is involved in the proteasome-mediated degradation of beta-catenin, through its interaction with beta-catenin, GSK-3 beta and Axin. APC also interacts with the microtubule cytoskeleton and has been localized to clusters near the distal ends of microtubules at the edges of migrating epithelial cells. Moreover, in Xenopus laevis epithelial cells, APC has been shown to move along microtubules and accumulate at their growing plus ends. 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 beta-catenin are transported along microtubules by KAP3-KIF3A-KIF3B, accumulate in the tips of membrane protrusions, and may thus regulate cell migration.
Jimbo
Takeshi
T
Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Kawasaki
Yoshihiro
Y
Koyama
Ryo
R
Sato
Rina
R
Takada
Shinji
S
Haraguchi
Keiko
K
Akiyama
Tetsu
T
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000818:Animals; D060466:Axin Protein; D001921:Brain / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism; D015723:Gene Library; D038362:Glycogen Synthase Kinase 3; D006657:Histones / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D016547:Kinesins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism; D012097:Repressor Proteins; D015534:Trans-Activators / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D029867:Xenopus Proteins; D014982:Xenopus laevis; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; C495266:CTNNB1 protein, Xenopus; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D006657:Histones; C097693:KAP3 protein, Crithidia fasciculata; C087415:KIF3A protein, human; C095899:KIF3B protein, human; D011506:Proteins; D015800:Protozoan Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D029867:Xenopus Proteins; C555454:axin1 protein, Xenopus; D051176:beta Catenin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D016547:Kinesins