RICS, a Novel GTPase-activating Protein for Cdc42 and Rac1, Is Involved in the β-Catenin-N-cadherin andN-Methyl-d-aspartate Receptor Signaling

Abstract

Cadherin adhesion molecules are believed to be important for synaptic plasticity. ␤-Catenin, which links cadherins and the actin cytoskeleton, is a modulator of cadherin adhesion and regulates synaptic structure and function. Here we show that ␤-catenin interacts with a novel GTPase-activating protein, named RICS, that acts on Cdc42 and Rac1. The RICS-␤-catenin complex was found to be associated with N-cadherin, N-methyl-D-aspartate receptors, and postsynaptic density-95, and localized to the postsynaptic density. Furthermore, the GTPase-activating protein activity of RICS was inhibited by phosphorylation by Ca 2؉ /calmodulin-dependent protein kinase II. These results suggest that RICS is involved in the synaptic adhesion-and N-methyl-D-aspartate-mediated organization of cytoskeletal networks and signal transduction. Thus, RICS may regulate dendritic spine morphology and strength by modulating Rho GTPases.Activity-induced changes in synaptic transmission efficacy, such as long term potentiation (LTP) 1 and long term depression, have been postulated to be involved in information storage during learning. Many studies have revealed that synaptic remodeling and plastic changes in dendritic spine morphology play a role in synaptic plasticity (1-6). Furthermore, changes in synaptic strength have been shown to involve the structural and functional modifications of the molecules present in the postsynaptic density (PSD) (7-10), an electrondense structure containing various structural and signaling molecules such as ion channels, scaffolding proteins, protein kinases, small G-proteins, cell adhesion proteins, and cytoskeletal proteins (11, 12).The cadherins are a family of single-pass transmembrane proteins that mediate Ca 2ϩ -dependent, homophilic intercellular adhesion (13). Some members of the cadherin family of adhesion proteins are localized to synaptic junctions and have been implicated in synaptic plasticity (14, 15). For example, inhibitory antibodies to the first extracellular domain of Ncadherin, one of the classical cadherins enriched in neural cells, have been shown to attenuate the induction of LTP (16,17). Also, antagonistic peptides containing the consensus sequence for cadherin dimer formation prevent the induction of LTP (16). Furthermore, inhibition of cadherin activity by a dominantnegative N-cadherin, as well as by mutation of ␣N-catenin, has been shown to alter dendritic spine morphology (18), suggesting that cadherins function as regulators of synaptic plasticity by modulating spine morphology.␤-Catenin interacts with the cytoplasmic domain of classical cadherins and links cadherins and the actin cytoskeleton (19,20). ␤-Catenin and N-cadherin are present in axons and dendrites prior to synapse formation and then cluster at developing synapses and form a symmetrical adhesion structure in synaptic junctions (21). Moreover, it has been reported recently (10) that neural activity induces redistribution of ␤-catenin from dendritic shafts into spines, where it interacts with cadherin to influence synaptic...

An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP

“…In vivo pull-down assays suggest that p250GAP potentially regulates several Rho family GTPases (16)(17)(18)(19)(20), and cerebellar granule cells from p250GAP-knockout mice show increased Cdc42 activity (18). p250GAP is enriched in the postsynaptic density where it interacts with the NMDA NR2B receptor subunit and the scaffold protein PSD-95 (25,26). p250GAP also interacts with Fyn (17), a tyrosine kinase that phosphorylates NR2B and regulates NMDA-dependent neuronal plasticity (27).…”

AMPA, not NMDA, activates RhoA GTPases and subsequetly phosphorylates moesin

“…Glutamate receptor and Rho GTPase have been proposed to be essential to dendrite growth in Xenopus (Sin et al, 2002). A Rho-GAP, RICS (Okabe et al, 2003) as well as several Rac/Cdc42-specific Rho-GEF, such as Kalirin-7 (Penzes et al, 2001), dPix (Parnas et al, 2002) and bPIX (Park et al, 2003), have been reported to play a role in dendrite remodeling. These reports are focusing on the involvement of Rho GTPases in dendritic morphogenesis through NMDA receptor and suggest that Rac and AMPA, not NMDA, activates RhoA GTPases and subsequetly phosphorylates m oesin Cdc42 activities enhance dendritic remodeling while RhoA activity inhibits (Wong et al, 2000;Li et al, 2002;Sin et al, 2002).…”

The PX-RICS-14-3-3ζ/θ Complex Couples N-cadherin-β-Catenin with Dynein-Dynactin to Mediate Its Export from the Endoplasmic Reticulum

“…RICS is expressed predominantly in neurons of the brain and localized to the growth cone and postsynaptic density, where it regulates neurite extension and presumably N-methyl-D-aspartate signaling (14). In contrast, PX-RICS is expressed in a wide variety of tissues and cell lines and localized to the ER and cis-Golgi (13,15).…”

“…Classic cadherins (simply referred to cadherins hereafter) (5-9), however, are known to have no functional ER export motifs, and their efficient ER exit requires complex formation with ␤-catenin at the ER immediately after cadherin synthesis (10 -12). We have recently shown that this ␤-catenin-facilitated ER export of cadherins requires PX-RICS, a ␤-catenininteracting GTPase-activating protein (GAP) for Cdc42 (13).PX-RICS is an alternatively spliced isoform of RICS (RhoGAP involved in the ␤-catenin-N-cadherin and N-methyl-D-aspartate receptor signaling) and contains phox homology (PX) and Src homology 3 domains in its N-terminal region (14,15). RICS is expressed predominantly in neurons of the brain and localized to the growth cone and postsynaptic density, where it regulates neurite extension and presumably N-methyl-D-aspartate signaling (14).…”

“…PX-RICS is an alternatively spliced isoform of RICS (RhoGAP involved in the ␤-catenin-N-cadherin and N-methyl-D-aspartate receptor signaling) and contains phox homology (PX) and Src homology 3 domains in its N-terminal region (14,15). RICS is expressed predominantly in neurons of the brain and localized to the growth cone and postsynaptic density, where it regulates neurite extension and presumably N-methyl-D-aspartate signaling (14).…”