Research for a protein tyrosine phosphatase for cell adhesion and its mutations in gastrointestinal cancers.

研究胃肠道癌症中细胞粘附的蛋白酪氨酸磷酸酶及其突变。

• 批准号: 09670549
• 负责人: MATOZAKI Takashi
• 金额: $ 2.05万
• 依托单位: Kobe University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670549/
• 关键词: Protein tyrosine phosphatase; PTPH1; Gastrointestinal cancer; Cell adhesion; PTPH1; Ezrin

Since the level of tyrosine phosphorylation is determined by the balance between the actions of both protein tyrosine kinases and protein tyrosine phosphatases (PTPases), not only the unregulated activation of PTKs but also the inactivation of PTPases may be involved in the malignant transformation of gastrointestinal cells. PTPH1 is a human non-transmembrane-type PTPase that has recently been molecularly cloned. This enzyme contains an Ezrin-like structure and a PDZ domain in its N-terminal region. Since Ezrin-like structures are suggested to be involved in cell adhesion, PTPH1 may locate at the cell adhesion sites and regulate cell adhesion through the control of tyrosine phosphorylation of proteins at cell adhesion sites. In this study, we investigated the physiological roles of PTPH1 and clinical applications of PTPH1. (1) PTPH1 located at cell adhesion sites. (2) Transfection of PTPH1 mutants into cultured cells did not show any changes in terms of cell adhesion. We will further examine the effect of microinjection of antibody to PTPH1 into cultured cells. (3) With the use of RT-P CR, we have examined the mutations of PTPH1 gene in various gastrointestinal cancers. We have found several mutations in PTPH1 gene in gastrointestinal cancer sample. We will further investigate whether the mutations found in gastrointestinal cancers results in oncogenesis of these cancers. In addition, we will try to identify the proteins bound to the Ezrin domain or the PDZ domain of PTPH1 by the yeast two-hybrid system.

由于酪氨酸磷酸化水平取决于蛋白酪氨酸激酶和蛋白酪氨酸磷酸酶（PTPases）之间的平衡，因此不仅PTKs的不受调节的激活而且PTPases的失活可能参与胃肠细胞的恶性转化。PTPH 1是最近被分子克隆的人非跨膜型PTPH。该酶在其N-末端区域含有Ezrin样结构和PDZ结构域。由于Ezrin样结构被认为参与细胞粘附，PTPH 1可能位于细胞粘附位点，并通过控制细胞粘附位点蛋白质的酪氨酸磷酸化来调节细胞粘附。在这项研究中，我们研究了PTPH 1的生理作用和PTPH 1的临床应用。(1)PTPH 1定位于细胞粘附部位。(2)将PTPH 1突变体转染到培养的细胞中，在细胞粘附方面没有显示出任何变化。我们将进一步研究向培养细胞中显微注射PTPH 1抗体的效果。(3)我们应用RT-PCR技术检测了多种胃肠道肿瘤中PTPH 1基因的突变。我们在胃肠道肿瘤标本中发现了PTPH 1基因的几个突变。我们将进一步研究在胃肠道癌症中发现的突变是否导致这些癌症的肿瘤发生。此外，我们将尝试通过酵母双杂交系统鉴定与PTPH 1的Ezrin结构域或PDZ结构域结合的蛋白。

项目成果

Takada,T.: "Roles of the complex formation of SHPS-1 with SHLP-2 in insulin-stimulated MAP kinase activation." J.Biol.Chem.273・15. 9234-9242 (1998)

Takada, T.：“SHPS-1 与 SHLP-2 的复合物形成在胰岛素刺激的 MAP 激酶激活中的作用。”J.Biol.Chem.273·15（1998）。

Kuroda, N.: "Differential expression of SHP2,a protein-tyrosine phosphatase with SRC homology-2 domins,in various types of renal tumor." Virchows Arch.433・4. 331-339 (1998)

Kuroda, N.：“SHP2（一种具有 SRC 同源性 2 结构域的蛋白质酪氨酸磷酸酶）在各种类型的肾肿瘤中的差异表达。”433·4 (1998)。

Takeda, H.: "Lysophosphatidic acid-induced association of SHP-2 with SHPS-1 : Roles of RHO,FAK,and SRC family kinase." Oncogene. 16. 3019-3028 (1998)

Takeda, H.：“溶血磷脂酸诱导的 SHP-2 与 SHPS-1 的关联：RHO、FAK 和 SRC 家族激酶的作用。”

Takeda, H.: "PI 3-kinase gamma and protein kinase C-zeta mediate RAS-independent activation of MAP kinase by a Gi protein-coupled receptor." EMBO J.18. 386-395 (1999)

Takeda, H.：“PI 3-激酶 gamma 和蛋白激酶 C-zeta 通过 Gi 蛋白偶联受体介导 MAP 激酶的 RAS 独立激活。”

Takeda,H.et al.: "Lycophosphatidic acid-induced association of SHP-2" Oncogene. (in press). (1998)

Takeda，H.et al.：“Lycophosphatidic Acid-induced Association of SHP-2”癌基因。