Leucine-rich repeat and PDZ [postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1] domain proteins such as scribble and Densin-180 have been implicated in the establishment of cell-cell contacts. Here, we show that Densin-180, which has been identified as a constituent of the postsynaptic density in excitatory synapses interacts with the postsynaptic scaffold protein shank (shank1-3). The interaction involves a two-point attachment of the C-terminal region of Densin-180 with the Src homology 3 domain and the N-terminal part of the proline-rich region of shank proteins. The N-terminal leucine-rich repeat region, which is not involved in binding shank, targets Densin-180 to the plasma membrane in transfected cells and to the basolateral membrane of epithelial cells. Nevertheless, coexpression of shank leads to a redirection of Densin-180 into intracellular clusters. In cultured hippocampal neurons, Densin-180 overexpression induces excessive branching of neuronal dendrites, which occurs at the expense of clusters for the postsynaptic marker PSD-95. Coexpression of shank3 abrogates branch formation and targets Densin-180 into postsynaptic clusters instead. Shank blocks binding of delta-catenin but not alphaCaM kinase II to Densin-180; because delta-catenin has been shown to induce branching and neurite formation, our data suggest a mechanism where shank could block the activation of a Densin-180-dependent signaling pathway by delta-catenin.