Signal transduction mechanism of proteoglycan-type tyrosine phosphatase PTPS

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PTP ζ/RPTP β is a proteoglycan-type receptor-like protein tyrosine phosphatase specifically expressed in the brain. It has been revealed that the extracellular domain of PTP ζ binds various extracellular matrix proteins (tenascin-C and tenascin-R), growth factors (pleiotrophin, midkine and FGF-2) and cell adhesion molecules (Nr-CAM, L1, F3, N-CAM and TAG-I). However, almost nothing is known about the intracellular signaling mechanism of PTP ζ including substrate molecules. In order to identify the proteins that interact with the intracellular region of PTP ζ , we performed yeast two-hybrid screening using the intracellular region of PTP ζ as a bait. By screening the rat brain cDNA library, we found that some of the PSD-95/SAP90 family proteins (PSD-95/SAP90, SAP97/hdlg and SAPIO2) interact with PTP ζ. These proteins are composed of three PDZ domains, a SH3 domain and a guanylate kinase (GK)-like domain, and are concentrated in the central synapses. The PDZ domains of this family bind to the specific cytoplasmic C-terminal sequences of several membrane proteins such as NMDA receptor and Shaker-type KィイD1+ィエD1 channel, mediating the protein-protein interaction to form large synaptic macromolecular complexes. Experiments using various deletion mutants of PTP ζand PSD-95 indicated that the C-terminal portion of PTP ζ binds to the second PDZ domain of PSD-95. Immunohistochemical analysis revealed that PTP ζ and PSD-95 are similarly distributed in the dendrites of pyramidal neurons of the hippocampus and neocortex. These results suggest that PTP ζ is involved in the regulation of synaptic function by forming postsynaptic macromolecular complexes with PSD-95.