Semaphorins are a family of secreted and membraneassociated proteins involved in growth cone guidance during development. Here, we describe the interaction of Semaphorin4F (Sema4F) with the post-synaptic density protein SAP90/ PSD-95. Using the yeast two-hybrid system and coprecipitation assays we were able to show an interaction between the extreme C-terminus of Sema4F and the PDZ domains of SAP90/PSD-95. Heterologous coexpression of a chimeric EphrinB1/Semaphorin4F protein with SAP90/PSD-95 in COS cells leads to translocation of SAP90/PSD-95 from the cytosol to the membrane. Deletion analysis shows that this translocation activity of Sema4F is completely dependent on the presence of the last three C-terminal amino acids. In addition, Sema4F immunoreactivity is present in synaptosome fractions and enriched in post-synaptic density fractions. Consistently, in cultured hippocampal neurons, we demonstrate punctate colocalization of Sema4F and SAP90/PSD-95 in dendrites, furthermore we found colocalization of Sema4F with synapsin1 suggesting a synaptic localization. Our data implicate a new functional context for semaphorins at glutamatergic synapses. Keywords: path ®nding, post-synaptic density, PSD-95, SAP90, semaphorin, synapse, synaptic plasticity.The semaphorins are a large family of secreted and membrane-bound proteins that are characterized by a conserved N-terminal located domain of < 500 amino acids, the sema domain (Kolodkin et al. 1993;Yu and Kolodkin 1999;Nakamura et al. 2000;Tamagnone and Comoglio 2000). According to their modular structure and membrane-binding capacity, semaphorins are divided into eight different classes (Semaphorin Nomenclature Committee 1999). Semaphorins play important roles in axon guidance, in the regulation of cell migration and angiogenesis (Behar et al. 1996;Kitsukawa et al. 1997), and in the modulation of the immune system (Hall et al. 1996;Delaire et al. 1998). Recent evidence shows additional functions of semaphorins in regulating neuronal apoptosis (Gagliardini and Fankhaus 1999;Shirvan et al. 1999) and metastatic growth of tumours (Yamada et al. 1997;Christensen et al. 1998). However, the function of semaphorins is best characterized as ensuring the correct connectivity of the nervous system during development (Mark et al. 1997). Only recently has there been major progress in identi®ying the signal transduction mechanisms of semaphorins. First, the neuropilins were identi®ed as transmembrane molecules binding class 3 semaphorins (Chen et al. 1997;He and Tessier-Lavigne 1997;Kolodkin et al. 1997). However, the cytoplasmic domain of neuropilin-1 is not necessary for Sema3A activity and consequently a second class of transmembrane semaphorin receptors was identi®ed, the plexins (Ohta et al. 1995;Comeau et al. 1998 Abbreviations used: DMEM, Dulbecco's modi®ed Eagle's medium; PBS, phosphate-buffered saline; PDZ, post-synaptic density protein-95, discs large protein, zonula occludens; PSD-95, post-synaptic density protein-95; SAP90, synapse associated protein 90; SDS2PA...
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