The Shank family of postsynaptic density proteins interacts with and promotes synaptic accumulation of the βPIX guanine nucleotide exchange factor for Rac1 and Cdc42

The Shank/ProSAP family of multidomain proteins is known to play an important role in organizing synaptic multiprotein complexes. Here we report a novel interaction between Shank and betaPIX, a guanine nucleotide exchange factor for the Rac1 and Cdc42 small GTPases. This interaction is mediated by the PDZ domain of Shank and the C-terminal leucine zipper domain and the PDZ domain-binding motif at the extreme C terminus of betaPIX. Shank colocalizes with betaPIX at excitatory synaptic sites in cultured neurons. In brain, Shank forms a complex with betaPIX and betaPIX-associated signaling molecules including p21-associated kinase (PAK), an effector kinase of Rac1/Cdc42. Importantly, overexpression of Shank in cultured neurons promotes synaptic accumulation of betaPIX and PAK. Considering the involvement of Rac1 and PAK in spine dynamics, these results suggest that Shank recruits betaPIX and PAK to spines for the regulation of postsynaptic structure.