Adenomatous polyposis coli (APC) tumor suppressor protein binds to microtubules, leading to microtubule bundling and stabilization. The protein also interacts with postsynaptic density (PSD)-95, a major scaffolding protein in neurons. Here, we analyzed the effects of PSD-95 on the microtubule-bundling activity of APC. The coexpression of APC and PSD-95 in COS-7 cells enhanced microtubule-bundle formation compared with the expression of APC alone. A mutant APC variant that does not associate with PSD-95 did not enhance microtubule bundling, despite coexpression with PSD-95. Immunoelectron microscopy showed that the APC-PSD-95 complex sometimes colocalized on microtubules in processes of cultured neurons. These results suggest that the microtubule-bundling activity of APC is regulated by its interaction with PSD-95, which might modulate microtubule architecture and dynamics in neurons. (c) 2006 Elsevier Ireland Ltd. All rights reserved.