The Shank Family of Postsynaptic Density Proteins Interacts with and Promotes Synaptic Accumulation of the βPIX Guanine Nucleotide Exchange Factor for Rac1 and Cdc42

Eunhye Park,Moonseok Na,Jeonghoon Choi,Seho Kim,Jae-Ran Lee,Jiyoung Yoon,Dongeun Park,Morgan Sheng,Eunjoon Kim

doi:10.1074/jbc.m301052200

Abstract

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 beta PIX, 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 beta PIX. Shank colocalizes with beta PIX at excitatory synaptic sites in cultured neurons. In brain, Shank forms a complex with beta PIX and beta PIX-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 beta PIX and PAK. Considering the involvement of Rac1 and PAK in spine dynamics, these results suggest that Shank recruits beta PIX and PAK to spines for the regulation of postsynaptic structure.

Highlights

Dendritic spines are actin-rich morphological specializations in neurons that mediate most excitatory synaptic transmission [1,2,3]
In light of the fact that Rac/Cdc42 and p21-activated kinase (PAK) regulate the actin cytoskeleton [28] and that dendritic spines are actin-rich structures [2], our results suggest that Shank recruits ␤PIX and ␤PIX-associated proteins to spines and regulates postsynaptic structure
Interaction between Shank and ␤PIX in Vitro—We reported recently [40] that ␤PIX is enriched in the postsynaptic density (PSD) and associates with the GIT-liprin-␣-GRIP complex that is involved in the regulation of synaptic targeting of alpha-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid glutamate receptors

Summary

Introduction

Dendritic spines are actin-rich morphological specializations in neurons that mediate most excitatory synaptic transmission [1,2,3]. In light of the fact that Rac/Cdc42 and PAK regulate the actin cytoskeleton [28] and that dendritic spines are actin-rich structures [2], our results suggest that Shank recruits ␤PIX and ␤PIX-associated proteins to spines and regulates postsynaptic structure. These results indicate that the LZ domain and the C-terminal PDZ-binding motif of ␤PIX mediate its interaction with Shank.

Results

Conclusion