Signal transduction mechanism of proteoglycan-type tyrosine phosphatase PTPS

PTPζ/RPTPβis a proteoglycan-type receptor-like protein tyrosine phosphatase specifically expressed in the brain.It has been revealed that the extracellular domain of PTPζbinds 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 PTPζincluding substrate molecules.In order to identify the proteins that interact with the intracellular region of PTPζ，we performed yeast two-hybrid screening using the intracellular region of PTPζas 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 PTPζ.These proteins are composed of three PDZ domains，a SH3domain 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 I D 1channel，mediating the protein-protein interaction to form large synaptic macromolecular complexes。Experiments using various deletion mutants of PTPζand PSD-95 indicated that the C-terminal portion of PTPζbinds to the second PDZ domain of PSD-95.Immunohistochemical analysis revealed that PTPζand PSD-95 are similarly distributed in the dendrites of pyramidal neurons of the hippocampus and neocortex.These results suggest that PTPζis involved in the regulation of synaptic function by forming postsynaptic macromolecular complexes with PSD-95.

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.