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调节中起重要作用。在未造成的正常时间内，即使在与HGF结合后，MET激活/酪氨酸磷酸化也会抑制。这不仅可以通过HGF结合，还可以通过细胞 - 细胞接触和细胞损伤来调节HGF依赖的MET受体激活。在这项研究中，研究了通过细胞细胞接触和SER985磷酸化在MET的近膜域中通过细胞 - 细胞接触和SER985磷酸化的抑制机制。1。在以稀疏的细胞密度培养的肝细胞中，HGF诱导长时间的MET激活和明显的有丝分裂反应。相比之下，HGF诱导的瞬态MET激活，但未能诱导与细胞细胞接触的汇合肝细胞中的有丝分裂反应。蛋白酪氨酸磷酸酶的表达，在汇合肝细胞中特别刺激HGF刺激后LAR增加。与Met和去磷酸化的Ty相关的LAR…更多的玫瑰磷酸化MET。 LAR和MET的功能关联是细胞 - 细胞接触抑制HGF依赖性MET激活的抑制机制的基础。2。在培养的肝细胞中，当Ser985被磷酸化时，抑制了HGF依赖性MET磷酸化/激活。在正常肝脏中，MET SER985被磷酸化，但是，Ser985在肝损伤（例如部分肝肝损伤）后被脱磷酸化。以相对于Ser985磷酸化的方式，在肝损伤后激活MET。结果表明，MET的近去膜结构域中的SER985受组织损伤的调节，并且在Met的近去膜膜结构域中的Ser985磷酸化可能是一种机制，在未受伤的器官中抑制了HGF依赖性MET激活。由于用judammbrane删除的MET接收器自然表达为剪接变体，因此Met的近去膜可能在调节HGF依赖性MET响应组织损伤的情况下起重要作用。3。使用转基因小鼠研究仅表达仅用juxtammbrane结构域删除的变体的转基因小鼠研究了MET和组织调节中MET的生理意义。较少的

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