The Junction-associated Protein AF-6 Interacts and Clusters with Specific Eph Receptor Tyrosine Kinases at Specialized Sites of Cell-Cell Contact in the Brain

doi:10.1083/jcb.144.2.361

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J. Cell Biol., Volume 144, Number 2, January 25, 1999 361-371

The Junction-associated Protein AF-6 Interacts and Clusters with Specific Eph Receptor Tyrosine Kinases at Specialized Sites of Cell-Cell Contact in the Brain

Michael Buchert,^* Stefan Schneider,^* Virginia Meskenaite,^§ Mark T. Adams,^* Eli Canaani,^¶ Thomas Baechi, Karin Moelling,^* and Christopher M. Hovens^*

^* Institut für Medizinische Virologie and Elektronenmikroskopisches Zentrallabor, Universität Zürich; ^§ Institut für Neuroinformatik, Universität Zürich/Eidgenössische Technische Hochschule, CH-8028 Zürich, Switzerland; and ^¶ Weizmann Institute for Science, Rehovot 76100, Israel

The AF-6/afadin protein, which contains a single PDZ domain, forms a peripheral component of cell membranes at specializedsites of cell-cell junctions. To identify potential receptor-bindingtargets of AF-6 we screened the PDZ domain of AF-6 against a rangeof COOH-terminal peptides selected from receptors having potentialPDZ domain-binding termini. The PDZ domain of AF-6 interacts witha subset of members of the Eph subfamily of RTKs via its COOHterminus both in vitro and in vivo. Cotransfection of a greenfluorescent protein-tagged AF-6 fusion protein with full-lengthEph receptors into heterologous cells induces a clustering ofthe Eph receptors and AF-6 at sites of cell-cell contact. Immunohistochemicalanalysis in the adult rat brain reveals coclustering of AF-6 withEph receptors at postsynaptic membrane sites of excitatory synapsesin the hippocampus. Furthermore, AF-6 is a substrate for a subgroupof Eph receptors and phosphorylation of AF-6 is dependent on afunctional kinase domain of the receptor. The physical interactionof endogenous AF-6 with Eph receptors is demonstrated by coimmunoprecipitationfrom whole rat brain lysates. AF-6 is a candidate for mediatingthe clustering of Eph receptors at postsynaptic specializationsin the adult ratbrain.

Key words: postsynaptic clustering; PDZ domains; receptor tyrosine kinases; neuron physiology; Ras-binding protein

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