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

HGF（肝细胞生长因子）和 Met/HGF 受体酪氨酸激酶在组织再生中发挥重要作用，即使在与 HGF 结合后，Met 激活/酪氨酸磷酸化也会受到抑制。因此，HGF 依赖性 Met 受体激活可能受到抑制。不仅受到 HGF 结合的调节，还受到细胞环境（例如细胞-细胞接触和细胞损伤）的调节。在这项研究中，Met 激活的抑制机制是通过细胞-细胞接触和 Ser985 磷酸化来实现的。研究了Met的近膜结构域。1．在稀疏细胞密度培养的肝细胞中，HGF诱导延长的Met激活和显着的促有丝分裂反应，相反，HGF诱导Met激活，但未能诱导细胞紧密的汇合瞬时肝细胞的促有丝分裂反应。 -细胞接触。HGF 刺激后，蛋白质酪氨酸磷酸酶 LAR 的表达增加，特别是在与 Met 和去磷酸化 ty 相关的汇合 LAR 中。 … 更多松氨酸磷酸化 Met。因此，LAR 和 Met 的功能关联是细胞与细胞接触抑制 HGF 依赖性 Met 激活的基础。2. 在培养的肝细胞中，HGF 依赖性 Met 酪氨酸磷酸化/激活受到抑制。当Ser985被磷酸化时，在正常肝脏中，Met Ser985被磷酸化，然而，在肝损伤（例如部分性损伤）后，Ser985被去磷酸化。与 Ser985 磷酸化相反，Met 在肝损伤后被激活。结果表明，Met 近膜结构域中的 Ser985 受到组织损伤的调节，并且 Met 近膜结构域中的 Ser985 磷酸化可能是 HGF- 的机制。由于近膜缺失的 Met 受体自然表达为剪接，因此依赖性 Met 激活在未受伤的器官中受到抑制。 Met的近膜结构域可能在响应组织损伤的HGF依赖性Met激活的调节中发挥重要作用。3．利用表达Met的转基因小鼠研究了Met的近膜结构域在发育和组织再生中的生理意义。唯一的Met变体与近膜结构域一起被删除。

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