The adenomatous polyposis coli gene (APC) is mutated in most colon can
cers. The APC protein binds lo the cellular adhesion molecule beta-cat
enin, which is a mammalian homolog of ARMADILLO, a component of the WI
NGLESS signaling pathway in Drosophila development. Here it is shown t
hat when beta-catenin is present in excess, APC binds to another compo
nent of the WINGLESS pathway, glycogen synthase kinase 3 beta (GSK3 be
ta), a mammalian homolog of Drosophila ZESTE WHITE 3. APC was a good s
ubstrate for GSK3 beta in vitro, and the phosphorylation sites were ma
pped to the central region of APC. Binding of beta-catenin to this reg
ion was dependent on phosphorylation by GSK3 beta.