Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3 beta phosphorylation

Truncation mutations in the adenomatous polyposis coli protein (APC) are re sponsible for familial polyposis, a form of inherited colon cancer. In addi tion to its role in mediating beta -catenin degradation in the Wnt signalin g pathway, APC plays a role in regulating microtubules. This was suggested by its localization to the end of dynamic microtubules in actively migratin g areas of cells and by the apparent correlation between the dissociation o f APC from polymerizing microtubules and their subsequent depolymerization [1, 2], The microtubule binding domain is deleted in the transforming mutat ions of APC [3, 4]; however, the direct effect of APC protein on microtubul es has never been examined. Here we show that binding of APC to microtubule s increases microtubule stability in vivo and in vitro. Deleting the previo usly identified microtubule binding site from the C-terminal domain of APC does not eliminate its binding to microtubules but decreases the ability of APC to stabilize them significantly. The interaction of APC with microtubu les is decreased by phosphorylation of APC by GSK3 beta, These data confirm the hypothesis that APC is involved in stabilizing microtubule ends. They also suggest that binding of APC to microtubules is mediated by at least tw o distinct sites and is regulated by phosphorylation.