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Regulation of tissue regeneration and homeostasis through ON-OFFcontrol of the Met/HGF receptor

通过 Met/HGF 受体的 ON-OFF 控制来调节组织再生和体内平衡

基本信息

批准号：
18570127
负责人：
MATSUMOTO Kunio
金额：
$ 2.63万
依托单位：
Kanazawa University (2007)Osaka University (2006)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18570127/
关键词：
HGF Met contact inhibition tissue regeneration knockout mouse protein tyrosine phosnhatase tyrosine kinase growth factor

项目摘要

HGF (hepatocyte growth factor) and Met/HGF receptor tyrosine kinase play important roles in tissue regeneration. In non-injured normal tissues, Met activation/tyrosine phosphorylation is suppressed even following binding with HGF. Thus, HGF-dependent Met receptor activation may be regulated by not only HGF-binding but also cellular context such as cell-cell contact and cellular injury. In this research, suppressive mechanisms of Met activation through cell-cell contact and Ser985 phosphorylation in the juxtamembrane domain of the Met were investigated.1. In hepatocytes cultured at a sparse cell density, HGF induced prolonged Met activation and a marked mitogenic response. In contrast, HGF induced transient Met activation but failed to induce mitogenic response in confluent hepatocytes with tight cell-cell contact. Expression of the protein tyrosine phosphatase, LAR increased following HGF-stimulation specifically in confluent hepatocytes. LAR associated with Met and dephosphorylated ty … More rosine-phosphorylated Met. Thus functional association of LAR and Met underlies the inhibitory mechanism by which HGF-dependent Met activation is suppressed by cell-cell contact.2. In hepatocytes in culture, HGF-dependent Met tyrosine phosphorylation/activation was inhibited when Ser985 was phosphorylated. In the normal liver, Met Ser985 was phosphorylated, however, Ser985 was dephosphorylated after hepatic injury such as partial hepatectomy. In reciprocal manner to Ser985 phosphorylation, Met was activated after hepatic injury. The results suggest that Ser985 in the juxtamembrane domain of Met is regulated by tissue injury and that Ser985 phosphorylation in the juxtamembrane domain of Met may be a mechanism by which HGF-dependent Met activation is suppressed in non-injured organs. Because Met receptor deleted with the juxtamembrane is naturally expressed as a splicing variant, the juxtamembrane of the Met may play an important role in regulation of HGF-dependent Met activation in response to tissue injury.3. Physiological significance of the juxtamembrane domain of Met in the development and tissue regeneration is investigated using the transgenic mice which express only variant Met deleted with the juxtamembrane domain. Less

肝细胞生长因子（HGF）和Met/HGF受体酪氨酸激酶在组织再生中起重要作用。在未损伤的正常组织中，即使在与HGF结合后，Met活化/酪氨酸磷酸化也受到抑制。因此，HGF依赖性Met受体活化不仅可以通过HGF结合调节，还可以通过细胞环境如细胞-细胞接触和细胞损伤调节。本研究通过细胞间接触和Met跨膜结构域Ser 985磷酸化来研究Met激活的抑制机制.在稀疏细胞密度下培养的肝细胞中，HGF诱导Met活化延长和显着的促有丝分裂反应。与此相反，肝细胞生长因子诱导短暂的Met激活，但未能诱导细胞间紧密接触的融合肝细胞的促有丝分裂反应。蛋白酪氨酸磷酸酶，LAR的表达增加后，HGF刺激，特别是在汇合的肝细胞。LAR与Met和去磷酸化ty相关 ...更多信息磷酸化蛋氨酸因此，LAR和Met的功能关联是细胞-细胞接触抑制HGF依赖性Met活化的抑制机制的基础.在培养的肝细胞中，当Ser 985被磷酸化时，HGF依赖的Met酪氨酸磷酸化/激活被抑制。在正常肝脏中，Met Ser 985被磷酸化，然而，Ser 985在肝损伤如部分肝切除后被去磷酸化。肝损伤后Met与Ser 985磷酸化呈交互作用。结果表明，丝氨酸985在甲硫氨酸的质膜结构域的组织损伤和丝氨酸985磷酸化的甲硫氨酸的质膜结构域可能是一种机制，通过这种机制，HGF依赖的甲硫氨酸激活被抑制在非损伤器官。由于Met受体与内膜缺失后天然表达为剪接变异体，因此Met的内膜可能在组织损伤后调节HGF依赖的Met活化中发挥重要作用.本研究利用仅表达缺失了甲硫氨酸跨膜结构域的变异体的转基因小鼠，研究了甲硫氨酸跨膜结构域在发育和组织再生中的生理意义。少

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hepatocyte growth factor attenuates cerebral ischemia-induced increase in permeability of blood-brain barrier and decreases in expression of tight junctional proteins in cerebral vessels.

肝细胞生长因子可减弱脑缺血引起的血脑屏障通透性增加和脑血管中紧密连接蛋白表达的减少。

DOI：
发表时间：
2006
期刊：
Neurosci Lett. 407
影响因子：
0
作者：
Date;I.;Takagi;N.;Takagi;K.;Tanonaka;K.;Funakoshi;H.;Matsumoto;K.;Nakamura;T.;akeo;S;Machide M. et al.;Sumi T.et al.;Matsumoto K. et al.;Namiki Y. et al.;Hosseinkhani H. et al.;Azuma J. et al.;Ogura Y. et al.;Tada T.et al.;Ono K.et al.;Niimura M. et al.;Date I.et al.
通讯作者：
Date I.et al.

NK4による血管新生阻害機槽:NK4による接着斑形成とフィプロネクチン構築の阻害

NK4抑制血管生成的机制：NK4抑制粘着斑形成和纤连蛋白组装