Research for physiological roles of protein tyrosine phosphatases for cell adhesion.

研究蛋白质酪氨酸磷酸酶对细胞粘附的生理作用。

• 批准号: 11670121
• 负责人: MATOZAKI Takashi
• 金额: $ 2.43万
• 依托单位: Gunma University (2000)Osaka University (1999)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670121/
• 关键词: Protein tyrosine phosphatase; SAP-1; SHP-2; PTPH1; Tyrosine phosphorylation; Cell adhesion; Ezrin; PDZ domain; 細胞運動

It has been suggested that tyrosine phosphorylation or dephosphorylation of proteins localized at cell-cell junctions plays an important role in the regulation of cell adhesion functions. We have been studying physiological roles of protein tyrosine phosphatases (PTPases) and discovered novel PTPases, such as SAP-1, SHP-2, and PTPH1. SAP-1 is a receptor-like PTPase, while SHP-2 is a non-transmembrane-type PTPase containing two SH2 domains. PTPH1 is also a non-transmembrane-type PTPase that contains an Ezrin-like structure and a PDZ domain in its N-terminal region. Thus, all these PTPases could be involved in the regulation of cell adhesion. In this study, we investigated the physiological roles of these three PTPases. The results obtained are follows :(1) Integrin-based cell adhesion directly regulates the catalytic activity of SAP-1. Expression of SAP-1 inhibits cell proliferation presumably through dephosphorylation of p130cas and other proteins localized at integrin-based cell adhesion sites. This inhibitory effect of SAP-1 may be related to "contact inhibition".(2) SHP-2 physiologically suppresses the activity of Rho and it thereby positively regulates the HGF/SF-induced cell scattering. In addition, Vav2 may be involved in the SHP-2-Rho pathway. We have generated knockout mice of SHPS-1, an SHP-2 substrate, and have shown that SHPS-1 is essential for the regulation of Ras and Rho.(3) We have tried to identify the proteins bound to the Ezrin domain or the PDZ domain of PTPH1 by the yeast two-hybrid system. We will analyze the function of these binding partners of PTPH1.

已有研究表明，细胞间连接蛋白的酪氨酸磷酸化或去磷酸化在调节细胞黏附功能中起着重要作用。我们一直在研究蛋白酪氨酸磷酸酶(PTPase)的生理作用，发现了新的PTPase，如SAP-1，SHP-2和PTPH1。SAP-1是一种受体样PTPase，而SHP-2是一种含有两个SH2结构域的非跨膜型PTPase。PTPH1也是一种非跨膜型PTPase，在其N-末端含有Ezrin样结构和PDZ结构域。因此，所有这些PTPase都可能参与细胞黏附的调节。在本研究中，我们研究了这三种PTPase的生理作用。研究结果如下：(1)基于整合素的细胞黏附直接调节SAP-1的催化活性。SAP-1的表达可能通过p130Cas和其他定位于基于整合素的细胞黏附位点的蛋白的去磷酸化来抑制细胞的增殖。SAP-1的这种抑制作用可能与“接触抑制”有关。(2)SHP-2生理性地抑制Rho的活性，从而正向调节HGF/SF诱导的细胞散射。此外，Vav2可能参与SHP-2-Rho通路。我们已经建立了SHP-2底物SHPS-1的敲除小鼠，并证明SHPS-1对于调节RAS和Rho是必不可少的。(3)我们试图通过酵母双杂交系统鉴定与PTPH1的Ezrin结构域或PDZ结构域结合的蛋白质。我们将分析PTPH1的这些结合伙伴的功能。

项目成果

Fukunaga K.: "The distribution and characterization of SHP-1, that binds protein tyrosine phosphatase SHP-2, in the human and rat brain"Biomed. Res.. 20・4. 197-203 (1999)

Fukunaga K.：“结合蛋白酪氨酸磷酸酶 SHP-2 的 SHP-1 在人类和大鼠大脑中的分布和特征”Biomed. 197-203 (1999)。

Kikyo, M.: "Cell-cell adhesion-mediated tyrosine phosphorylation of nectin-2δ, an immunoglobulin-like cell adhesion molecule at adherens junctions."Oncogene. 17. 4022-4028 (2000)

Kikyo, M.：“细胞粘附介导的 nectin-2δ 酪氨酸磷酸化，这是一种粘附连接处的免疫球蛋白样细胞粘附分子。”17. 4022-4028 (2000)。

Takai,Y: "Small GTP-binding proteins"Physiol.Rev.. 81. 153-208 (2001)

Takai，Y：“小 GTP 结合蛋白”Physiol.Rev.. 81. 153-208 (2001)

Takai, Y: "Small GTP-binding proteins."Physiol.Rev.. 81. 153-208 (2001)

Takai, Y：“小 GTP 结合蛋白。”Physiol.Rev.. 81. 153-208 (2001)

Inagaki K.: "Roles for the protein tyrosine phosphatase SHP-2 in cytoskeletal organization, cell adhesion, and cell migration revealed by overexpression of a dominant negative mutant"Oncogene. 19・1. 75-84 (2000)

Inagaki K.：“通过显性失活突变体的过度表达揭示蛋白质酪氨酸磷酸酶 SHP-2 在细胞骨架组织、细胞粘附和细胞迁移中的作用”Oncogene 75-84 (2000)。