Study of laminin-5 in keratinocyte migration

Laminin-5在角质形成细胞迁移中的研究

• 批准号: 14570798
• 负责人: UTANI Atsushi
• 金额: $ 2.24万
• 依托单位: Chiba university
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570798/
• 关键词: Matrix; laminin-5; MMP; MAPK; ラミニン; シンデカン

The LG4 module of the laminin a3 chain (a3 LG4), a component of epithelial-specific laminin-5, has cell attachment activity and binds syndecan. Here, we show that recombinant a3 LG4 and a 19-mer synthetic peptide (A3G756) within a3 LG4 active for syndecan binding increased the expression of matrix metalloproteinase-1 (MMP-1) in keratinocytes and fibroblasts. This induction was inhibited by heparin and required de novo synthesis of proteins. In keratinocytes, A3G756 upregulated IL-1b and MMP-1 expression and an IL-1 receptor antagonist thoroughly inhibited A3G756-mediated induction of MMP-1. A3G756 also activated p38 mitogen-activated protein kinase (p38MAPK) and extracellular signal-related kinase (Erk). Studies with specific inhibitors of MAPKs showed that p38MAPK activation was necessary for both IL-1b and MMP-1 induction, but Erk activation was required only for MMP-1 induction. In fibroblasts, IL-1 receptor antagonist did not block A3G756-mediated induction of MMP-1. These results indicated that induction of MMP-1 by a3 LG4 is mediated through the IL-1b autocrine loop in keratinocytes but the mechanism of the induction in fibroblasts is different. Our study suggests that the laminin a3 LG4 module may play an important role in tissue remodeling by inducing MMP-1 expression during wound healing.

层粘连蛋白A3链的LG4模块(A3LG4)是上皮细胞特异性层粘连蛋白-5的组成部分，具有细胞黏附活性，并与Syndecan结合。在这里，我们发现重组A3LG4和A3LG4中的一个19聚体合成肽(A3G756)具有与Syndecan结合的活性，增加了角质形成细胞和成纤维细胞中基质金属蛋白酶-1(MMP1)的表达。这种诱导被肝素抑制，需要蛋白质从头合成。在角质形成细胞中，A3G756上调IL-1b和基质金属蛋白酶-1的表达，IL-1受体拮抗剂完全抑制A3G756介导的基质金属蛋白酶-1的诱导。A3G756还激活了p38丝裂原活化蛋白激酶(P38MAPK)和细胞外信号相关激酶(ERK)。对MAPKs特异性抑制剂的研究表明，p38MAPK的激活对于IL-1b和MMP1的诱导都是必需的，而ERK的激活只对MMP1的诱导是必需的。在成纤维细胞中，IL-1受体拮抗剂不能阻断A3G756介导的基质金属蛋白酶-1的诱导。这些结果表明，A3LG4通过角质形成细胞的IL-1b自分泌环诱导基质金属蛋白酶-1的产生，但在成纤维细胞中的诱导机制不同。我们的研究提示，层粘连蛋白A3LG4模块可能通过在伤口愈合过程中诱导基质金属蛋白酶-1的表达而在组织重塑中发挥重要作用。

项目成果

Matsuura H, Momota Y, et al.: "Localization of the laminin α4 chain in the skin and identification of a heparin-dependent cell adhesion site"J Invest Dermatol. (In press). (2004)

Matsuura H、Momota Y 等人：“皮肤中层粘连蛋白 α4 链的定位和肝素依赖性细胞粘附位点的识别”J Invest Dermatol（印刷中）。

Matsuura H, Momota Y, Murata K, Matsushima H, Suzuki N, Nomizu M, Shinkai H, Utani A.: "Localization of the laminin a4 chain in the skin and identification of a heparin-dependent cell adhesion site within the laminin a4 chain C-terminal LG4 module."J Inve

Matsuura H、Momota Y、Murata K、Matsushima H、Suzuki N、Nomizu M、Shinkai H、Utani A.：“层粘连蛋白 a4 链在皮肤中的定位以及层粘连蛋白 a4 链内肝素依赖性细胞粘附位点的鉴定

Suzuki N, Ichikawa N, Kasai S, Yamada M, Nishi N, Morioka H, Yamashita H, Kitagawa Y, Utani A, Hoffman MP, Nomizu M.: "Syndecan binding sites on the laminin a1 chain G domain."Biochemistry. 42. 12625-12633 (2003)

Suzuki N、Ichikawa N、Kasai S、Yamada M、Nishi N、Morioka H、Yamashita H、Kitakawa Y、Utani A、Hoffman MP、Nomizu M.：“层粘连蛋白 a1 链 G 结构域上的 Syndecan 结合位点。”生物化学。

Utani A, Momota Y, Endo H, Kasuya Y, Beck K, Suzuki N, Nomizu M, Shinkai H.: "Laminin a3 LG4 module induces matrix metalloproteinase 1 (MMP1) through MAPK signaling."J Biol Chem. 278. 34483-34490 (2003)

Utani A、Momota Y、Endo H、Kasuya Y、Beck K、Suzuki N、Nomizu M、Shinkai H.：“层粘连蛋白 a3 LG4 模块通过 MAPK 信号诱导基质金属蛋白酶 1 (MMP1)。”J Biol Chem。

OKAZAKI I, SUZUKI N, et al.: "Identification of Biologically active sequences in the laminin α4 chain G domain"J. Biol. Chem.. 277. 37070-37078 (2002)

OKAZAKI I、SUZUKI N 等人：“层粘连蛋白 α4 链 G 结构域中的生物活性序列的鉴定”J. Biol. 277. 37070-37078 (2002)