Study of signaling pathways mediated by tyrosine phosphorylation and regulate cadherin-dependent cell adhesion and cytoskeletal organization

酪氨酸磷酸化介导的信号通路及调节钙粘蛋白依赖性细胞粘附和细胞骨架组织的研究

• 批准号: 05454168
• 负责人: HAMABUCHI Michinari
• 金额: $ 4.16万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05454168/
• 关键词: tyrosine phosphorylation; cell adhesion; cytoskeletal structure; MMP-2; src; カドヘリン; カテニン; αカテニン; p60^<v-src>; src

This project was aimed to study signaling pathways activated by tyrosine phosphorylation and critical for the regulation of cell-cell adhesion and cytoskeletal organization. Tyrosine kinases were originally identifued as a product of oncogenes. However, later studies revealed that tyrosine kinases are also responsible for a wide variety of biological responce such as growth and differentiation of cells, immune responce and platelet aggregation. Despite it importance, precice biochemical precesses required for these responces remain largely unclear. To obtain a clue, we have developed a specific serum that recognize phosphotyrosine residue, and studied growth stimulation and cytoskeletal organization of transformed cells.In this study, we showed direct evidence that transformation by src activates MMP-2 which catalyzes degradation of extracellular matrix. We found that activation of MMP-2 directly correlates with transforming activity of src and can be inhibited by IFN treatment of cells. We also found that heavy metals can activate c-Src kinase and activated Src forms giant protein complex with other tyrosine phosphorylated proteines that associates with cytoskeletal structure.

该项目旨在研究酪氨酸磷酸化激活的信号通路，该通路对细胞间粘附和细胞骨架组织的调节至关重要。酪氨酸激酶最初被鉴定为癌基因的产物。然而，后来的研究表明，酪氨酸激酶还负责多种生物反应，例如细胞生长和分化、免疫反应和血小板聚集。尽管很重要，但这些反应所需的精确生化过程在很大程度上仍不清楚。为了获得线索，我们开发了一种识别磷酸酪氨酸残基的特异性血清，并研究了转化细胞的生长刺激和细胞骨架组织。在这项研究中，我们展示了直接证据表明src转化会激活MMP-2，从而催化细胞外基质的降解。我们发现MMP-2的激活与src的转化活性直接相关，并且可以被细胞的IFN处理所抑制。我们还发现重金属可以激活c-Src激酶，激活的Src与其他与细胞骨架结构相关的酪氨酸磷酸化蛋白形成巨型蛋白复合物。

项目成果

Hiroyuki Iwata et al.: "Abundant but inactive‐state gp140proto‐trk is expressed in neuroblastoma of patients with good prognosis" Jpn.J.Cancer Res.85. 32-39 (1994)

Hiroyuki Iwata 等人：“预后良好的患者的神经母细胞瘤中表达丰富但非活性状态的 gp140proto-trk”Jpn.J.Cancer Res.85 (1994)。

M.Hamaguchi et.al.: "p60^<v-src> causes tyrosine phospharylation and inactivation of the N-cadherin-catenin cell adhesion sistem." The EMBO Journal. 21. 307-314 (1993)

M.Hamaguchi 等人：“p60^<v-src> 导致酪氨酸磷酸化和 N-钙粘蛋白-连环蛋白细胞粘附系统失活。”

Katano,Y.et al: "Evidence of redox-linked signaling for prouducing a giant signal complex." J.Cell biochem.57. 432-439 (1995)

Katano, Y.等人：“氧化还原相关信号传导产生巨大信号复合物的证据。”

浜口道成: "癌治療のあゆみ" 財)がん集学的治療研究財団,

Michinari Hamaguchi：“癌症治疗的历史”癌症多学科治疗研究基金会，

Hengyi Xiao et al.: "Expression and tyrosine phosphorylation of phosphatidyl‐inositol 3 kinase in human gastric cancer cells;its correlation with growth" Int.J.Oncology. 6. 405-411 (1995)

Hengyi Shaw 等人：“人胃癌细胞中磷脂酰肌醇 3 激酶的表达和酪氨酸磷酸化；其与生长的相关性”Int.J.Oncology 6. 405-411 (1995)。