Signal transduction mechanism of proteoglycan-type tyrosine phosphatase PTPS

蛋白聚糖型酪氨酸磷酸酶PTPS的信号转导机制

• 批准号: 10680680
• 负责人: MAEDA Nobuaki
• 金额: $ 2.18万
• 依托单位: Okazaki National Research Institute
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10680680/
• 关键词: Proteoglycan; PTPζ; pleiotrophin; PSD-95; yeast two-hybrid system; 酵母two hybrid system; PTPS; 神経細胞; 細胞移動

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.

PTpζ/rptpβ是一种蛋白多糖型受体样蛋白酪氨酸磷酸酶，在大脑中特异表达。ζ胞外区可与多种细胞外基质蛋白(Tenascin-C和Tenascin-R)、生长因子(多营养素、中期因子和成纤维细胞生长因子-2)以及细胞黏附分子(Nr-CAM、L1、F3、N-CAM和Tag-I)结合。然而，对包括底物分子在内的pTPζ的细胞内信号机制几乎一无所知。为了鉴定与pTPζ胞内区相互作用的蛋白质，我们以pTPζ胞内区为诱饵，进行了酵母双杂交筛选。通过对大鼠脑ζ文库的筛选，我们发现一些PSD-95/SAP90家族蛋白(PSD-95/SAP90、SAP97/HDLG和SAPIO2)与PtP DNA相互作用。这些蛋白由三个PDZ结构域、一个SH3结构域和一个鸟苷酸激酶(GK)样结构域组成，集中在中央突触中。该家族的PDZ结构域与N-甲基-D-天冬氨酸受体、Shaker型K-ィイD_1+ィエD_1通道等几种膜蛋白的胞质C-末端序列结合，介导蛋白质-蛋白质相互作用形成大的突触大分子复合体。用PtPζ和Psd-95的各种缺失突变体进行的实验表明，PtPζ的C末端部分与Psd-95的第二个PDZ结构域结合。免疫组织化学分析显示，PtP、ζ和PsD-95在海马和新皮质锥体神经元树突中的分布相似。这些结果提示，PtPζ通过与PsD-95形成突触后大分子复合体参与突触功能的调节。

项目成果

Yamakawa, T.: "Levels of expression of pleistrophin and protein tyrosine phosphatase ζ are decreased in human colorectal cancers"Cancer Letterrs. 135. 91-96 (1999)

Yamakawa, T.：“人类结直肠癌中长链蛋白和蛋白酪氨酸磷酸酶 ζ 的表达水平降低”《癌症快报》135. 91-96 (1999)。

Kawachi, H. et al.: "Protein tyrosine phosphates ζ/RPTP β interacts with PSD-95/SAP90 family."Molealan Brain Research. 72. 47-54 (1999)

Kawachi, H. 等人：“蛋白质酪氨酸磷酸 ze/RPTP β 与 PSD-95/SAP90 家族相互作用。”Molealan Brain Research。

Revest, J. -M.: "The interaction between F3 immunoglobulin domains and protein tyrosine phosphatare ζ/β triggers bidirectional signalling between neurons and glial cells"European Journal of Newrosience. 11. 1134-1147 (1999)

Revest, J. -M.：“F3 免疫球蛋白结构域和蛋白酪氨酸磷酸 ζ/β 之间的相互作用触发神经元和神经胶质细胞之间的双向信号传导”《欧洲新闻杂志》11. 1134-1147 (1999)。

Revest, J.-M.: "The interaction between F3 immunoglebulin domains and protein tyrosine phosphatase ζ/β triggers bidirectional signalling between neurons and glice"European Journal of Neuroscience. 11. 1134-1147 (1999)

Revest, J.-M.：“F3 免疫球蛋白结构域和蛋白酪氨酸磷酸酶 ζ/β 之间的相互作用触发神经元和神经胶质细胞之间的双向信号传导”《欧洲神经科学杂志》11. 1134-1147 (1999)。

Yamakawa, T. et al.: "Levels of expression of pleiotrophin and protein tyrosine phosphatase ζ are decreased in human colorectal cancers."Cancer Letters. 135. 91-96 (1999)

Yamakawa, T. 等人：“人类结肠直肠癌中多效蛋白和蛋白酪氨酸磷酸酶 的表达水平降低。”Cancer Letters。135. 91-96 (1999)