Analysis of regulatory mechanism for cell polarity formation by JNK binding molecules during migration

JNK结合分子迁移过程中细胞极性形成的调控机制分析

基本信息

批准号：
16590241
负责人：
TAKINO Takahisa
金额：
$ 2.37万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590241/
关键词：
Cancer Invasion Cell Migration MAPK JNK ERK MT1-MMP Extracellular Matrix 情報伝達細胞極性インテグリン FAK

项目摘要

JNK/SAPK-associated protein 1(JSAP1) mediated an association between focal adhesion kinase (FAK) and JNK, which was induced by either co-expression of Src or attachment of cells to fibronectin (FN). Complex formation of FAK with JSAP1 and p130 Crk-associated substrate (p130^<Cas>) resulted in augmentation of FAK activity and phosphorylation of both JSAP1 and p130^<Cas>, which required p130^<Cas> hyperphosphorylation and was abolished by inhibition of Src. JNK activation by FN was enhanced by JSAP1, which was suppressed by disrupting the FAK/p130^<Cas> pathway by expression of a dominant-negative form of p130^<Cas> or by inhibiting Src. JSAP1 was co-localized with JNK and phosphorylated FAK at the leading edge and stimulated of cell migration, which depended on its JNK binding domain and was suppressed by inhibition of JNK. The level of JSAP1 mRNA correlated with advanced malignancy in brain tumors, unlike other JIPs. We propose that the JSAP1/FAK complex functions cooperatively as a sc … More affold for the JNK signaling pathway and regulator of cell migration on FN, and we suggest that JSAP1 is also associated with malignancy in brain tumors.MT1-MMP expression promoted FN-induced cell migration, which was accompanied by FN degradation and reduction of stable focal adhesions, which function as anchors for actin-stress fibers, and attenuated integrin clustering. The attenuation of integrin clustering was abrogated by MT1-MMP inhibition. When cultured on fibronectin, HT1080 cells, which endogenously express MT1-MMP, showed so-called motile morphology with well-organized focal adhesion formation, well-oriented actin-stress fiber formation and the lysis of FN through trails of cell migration. Inhibition of endogenous MT1-MMP resulted in the suppression of FN lysis and cell migration and promotion of stable focal adhesion formation concomitant with enhanced phosphorylation of tyrosine 397 of FAK and reduced ERK activation. These results suggest that lysis of the extracellular matrix by MT1-MMP promotes focal adhesion turnover and subsequent ERK activation, which in turn stimulates cell migration. Less

JNK/SAPK相关蛋白1（JSAP1）介导了焦点粘合剂激酶（FAK）和JNK之间的关联，这是由SRC共表达或细胞附着在纤连蛋白（FN）上引起的。 FAK与JSAP1和P130 CRK相关的底物（P130^<cas>）的复合形成导致FAK活性的增强和JSAP1和P130^<cas>的磷酸化，这需要P130^<CAS> CAS>过度磷酸化，并通过抑制SRC进行了废除。 JSAP1增强了FN的JNK激活，通过表达P130^<cas>的显性阴性形式或抑制SRC，通过破坏FAK/P130^<cas>途径来抑制FN。 JSAP1与JNK共定位，并在前缘磷酸化FAK并刺激细胞迁移，这取决于其JNK结合结构域，并通过抑制JNK抑制。与其他JIP不同，JSAP1 mRNA的水平与脑肿瘤的晚期恶性肿瘤相关。 We propose that the JSAP1/FAK complex functions cooperatively as a sc … More affect for the JNK signaling pathway and regulator of cell migration on FN, and we suggest that JSAP1 is also associated with malignancy in brain tumors.MT1-MMP expression promoted FN-induced cell migration, which was accomplished by FN degradation and reduction of stable focal adhesives, which function as anchors for actin-stress纤维，并减弱整联蛋白聚类。整联蛋白聚类的衰减被MT1-MMP抑制消除了。当在纤连蛋白上培养时，内源表达MT1-MMP的HT1080细胞显示出所谓的运动形态，其组织良好的局灶性粘附形成，良好的导向肌动蛋白压力纤维形成以及FN通过细胞迁移的踪迹裂解FN。内源性MT1-MMP的抑制导致FN裂解和细胞迁移的抑制，并促进稳定的局灶性粘合剂形成与FAK酪氨酸397的磷酸化增强和ERK激活减少。这些结果表明，MT1-MMP对细胞外基质的裂解促进了局灶性粘合剂的转移和随后的ERK激活，从而刺激细胞迁移。较少的

项目成果

期刊论文数量（31）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Increased matrix metalloproteinase-2 and membrane type 1 matrix metalloproteinase activity and expression in heterotopically transplanted murine tracheas.

DOI：
10.1016/s1053-2498(03)00112-8
发表时间：
2004-02
期刊：
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
影响因子：
0
作者：
N. Inaki;Y. Tsunezuka;K. Kawakami;Hiroshi Sato;T. Takino;M. Oda;G. Watanabe
通讯作者：
N. Inaki;Y. Tsunezuka;K. Kawakami;Hiroshi Sato;T. Takino;M. Oda;G. Watanabe

Cleavage of amyloid-precursor protein(APP)by membrane-type matrix metalloproteinases.

膜型基质金属蛋白酶裂解淀粉样前体蛋白（APP）。