V

neurexin syndecan j neuroligin / GKAP (SAPAP) / Rap1 GEF y\ NMDAR \ MAGUIN \ PIPase \ 5-catenin cytoplasmic ß-catenin \

Wnt signaling

Figure 5.2. Classic Cadherin Extracellular and Intracellular Binding Interactions. This list, while not exhaustive, illustrates the enormous variety of signaling interactions and regulatory mechanisms associated with cadherins. Transmembrane proteins are written in light gray and cytosolic proteins, in black. Some secondary and tertiary interactions are included to indicate known and potential mechanisms for cross-talk between cadherins and other systems. Data are taken principally from refs 18,69. Abbreviations: AKAP: A-kinase anchoring protein, ARVCF: armadillo repeat gene deletes in velocardiofacial syndrome, Ca2+/CaM:calcium-calmodulin, c-Abl: Abelson tyrosine kinase, CASK: calcium/calmodulin-dependent serine protein kinase, Cdk: cyclin-dependent kinase, ERBIN: ErbB2-interacting protein, Fer: Fer kinase, FGFR: fibroblast growth factor receptor, GEF: GTP exchange factor, GKAP: G kinase anchoring protein, IQGAP: GTPase activating protein with IQ motifs, MAGI: membrane-associated guanylate kinase, MAGUIN: membrane-associated guanylate kinase-interacting protein, MALS: mammalian LIN-7, PKA: protein kinase A, PKC: protein kinase C, PP2B: protein phosphatase 2B, PSD95: postsynaptic density protein 95 (also SAP90), PTP: protein tyrosine phosphatase, SAPAP: SAP90/PSD-95-associated protein, SAP: synapse-associated protein, Shc: SRC homology 2 domain containing (transforming protein-1), SHP2: SRC homology 2 domain-containing tyrosine phosphatase, S-SCAM: synaptic scaffolding molecule, Veli: vertebrate homolog of LIN-7, Wnt: wingless type, ZO-1: zona occludens 1.

which key cadherin-binding partners have been delated selectively in the nervous system or late in development show normal cadherin distribution surprisingly undisturbed at synapses14,15. Binding between cadherins can be blocked or attenuated by exposure to peptides containing HAV, highly conserved sequence in the EC1 domain of all type I classic cadherins. Some crystal structure data support that the HAV motif is at the trans-binding interface7, while more recent work has called this into question11. HAV-containing peptides are more effective at blocking A-cadherin-mediated axon extension for a variety of neuron types and systems than the assembly of cell-cell junctions16,17, suggesting that the cadherin interactions supporting outgrowth and junctional adhesion are likely to be different and may explain some of the apparent contradictions in the literature. Membrane-targeted cadherin mutants lacking the extracellular domain act as pan-cadherin-interfering proteins in vivo and in culture. The effects of such mutants appear to be potent and quite specific for classic cadherins. Mutants lacking the intracellular domain act as dominant-interfering proteins for individual cadherins, but there are some data that the extracellular domain can be adhesive on its own18,19. While it is clear that loss of all intracellular interactions abrogates many cadherin functions20, the contributions of particular family members are likely to become clearer with the increased use of RNAi to selectively decrease the levels of single cadherins. Cell-permeant peptides directed against particular intracellular domains appear to act as sinks for the normal cadherin-binding partners and have been used to help dissect differences in the actions of proteins binding the juxtamembrane or G-catenin binding domains21. Their actions are immediate but cell wide, affecting both cytoplasmic and membrane-bound pools of proteins.

Extracellular binding provokes cadherin binding to the actin cytoskeleton in a Rac1-dependent fashion in non-neuronal cells22 and this inhibits RhoA23. The srength of adhesion can be modulated by binding interactions with the catenin proteins which in the case of G-catenin is negatively regulated by its phosphorylation (Figure 5.2). G-catenin interacts with an enormous variety of scaffolding, signaling, and transmembrane proteins in addition to its interactions with cadherins and actin, thereby linking adhesion and ion channel activity at the cell surface to intracellular signaling pathways. For example, the LAR receptor protein tyrosine phosphatase co-immunoprecipitates with the cadherin-G-catenin complex as well as with the AMPA receptor-binding protein, GRIP. Mutations in LAR disrupting either its function or binding interactions reduce the synaptic localization of G-catenin as well as the surface concentration of AMPA receptors, suggesting that cadherin-catenin interactions may regulate AMPA receptor concentration24. Changes in activity can also modulate cadherin interactions. When neurons are exposed to NMDA, interactions between A-cadherin and the PKA-binding protein, AKAP79/150, are disrupted while A-cadherin homophilic binding is strengthened25. Since AKAP79/150 also binds to PSD95/SAP90 which binds directly to NMDA receptors, NMDA exposure may sever the connection between cadherins and NMDA receptors26 (Figure 5.2). These findings and others indicate that cadherin function is coupled actively to neurotransmission.

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