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) 介导粘着斑激酶 (FAK) 和 JNK 之间的关联，这种关联是通过 Src 的共表达或细胞与纤连蛋白 (FN) 的附着而诱导的，FAK 与 JSAP1 和 JSAP1 形成复合物。 p130 Crk 相关底物 (p130^<Cas>) 导致 FAK 活性增强以及 JSAP1 和 p130^<Cas> 磷酸化，这需要p130^<Cas> 过度磷酸化，并通过 JSAP1 增强 FN 抑制 Src 激活而消除，而 JSAP1 则通过 p130^<Cas 的显性失活形式的表达破坏 FAK/p130^<Cas> 途径来抑制。 > 或通过抑制 Src 与 JNK 和磷酸化 FAK 共定位于前缘并刺激细胞迁移，这取决于其 JNK 结合域和与其他 JIP 不同，JSAP1 mRNA 的水平与脑肿瘤的晚期恶性肿瘤相关，我们认为 JSAP1/FAK 复合物协同作用，作为 JNK 信号通路和细胞迁移的调节因子。 MT1-MMP 表达促进 FN 诱导的细胞迁移，同时伴随 FN 降解和稳定粘着斑减少，当在纤连蛋白上培养时，内源性表达 MT1-MMP 的 HT1080 细胞表现出所谓的运动形态。组织良好的粘着斑形成、定向肌动蛋白应力纤维形成以及 FN 的裂解抑制内源性 MT1-MMP 会抑制 FN 裂解和细胞迁移，并促进稳定的粘着斑形成，同时增强 FAK 的酪氨酸 397 磷酸化并减少 ERK 活化。 MT1-MMP 促进粘着斑更新和随后的 ERK 激活，从而刺激细胞迁移。

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）。