A novel signaling pathway of tissue kallikrein in promoting keratinocyte migration: activation of proteinase-activated receptor 1 and epidermal growth factor receptor.
A novel signaling pathway of tissue kallikrein in promoting keratinocyte migration: activation of proteinase-activated receptor 1 and epidermal growth factor receptor.
复制标题
DOI：
10.1016/j.yexcr.2009.10.022
复制
发表时间：
2010-02-01
影响因子：
3.7
通讯作者：
Chao J
中科院分区：
文献类型：
--
作者：
Gao L;Chao L;Chao J
组织激肽激酶（TK, KLK1）的生物学功能主要通过激肽生成和随后的激肽B2受体激活介导。在这项研究中，我们研究了TK及其信号通路在培养的人角质形成细胞迁移和大鼠皮肤伤口愈合模型中的潜在作用。在此，我们发现TK以浓度和时间依赖的方式促进细胞迁移和增殖。失活TK或激肽对细胞迁移无显著影响。有趣的是，活性TK诱导的细胞迁移没有被icatibant或L-NAME阻断，表明这一事件不依赖于kinin B2受体和一氧化氮的形成。蛋白酶激活受体1 （PAR1）小干扰RNA和PAR1抑制剂可抑制TK对细胞迁移的刺激作用。tk诱导的迁移与表皮生长因子受体（EGFR）和细胞外信号调节激酶（ERK）磷酸化增加有关，该磷酸化被蛋白激酶C （PKC）、Src、EGFR和ERK的抑制所阻断。tk诱导的细胞迁移和EGFR磷酸化被金属蛋白酶（MMP）抑制剂、肝素、抗EGFR外部结构域抗体、肝素结合的egf样生长因子（HB-EGF）和双调节蛋白（AR）阻断。局部应用TK可促进大鼠皮肤创面愈合，而icatibant和EGFR抑制剂可阻断TK的作用。抑酶蛋白和中和性tk抗体进一步延缓皮肤创面愈合。本研究揭示了TK在皮肤创面愈合中的新作用，揭示了TK通过激活PAR1-PKC-Src-MMP通路和HB-EGF/AR脱落依赖性EGFR转激活促进角质形成细胞迁移的新信号通路。
Biological functions of tissue kallikrein (TK, KLK1) are mainly mediated by kinin generation and subsequent kinin B2 receptor activation. In this study, we investigated the potential role of TK and its signaling pathways in cultured human keratinocyte migration and in a rat skin wound healing model. Herein, we show that TK promoted cell migration and proliferation in a concentration- and time-dependent manner. Inactive TK or kinin had no significant effect on cell migration. Interestingly, cell migration induced by active TK was not blocked by icatibant or L-NAME, indicating an event independent of kinin B2 receptor and nitric oxide formation. TK's stimulatory effect on cell migration was inhibited by small interfering RNA for proteinase-activated receptor 1 (PAR1), and by PAR1 inhibitor. TK-induced migration was associated with increased phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK), which was blocked by inhibition of protein kinase C (PKC), Src, EGFR and ERK. TK-induced cell migration and EGFR phosphorylation were blocked by metalloproteinase (MMP) inhibitor, heparin, and antibodies against EGFR external domain, heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin (AR). Local application of TK promoted skin wound healing in rats, whereas icatibant and EGFR inhibitor blocked TK's effect. Skin wound healing was further delayed by aprotinin and neutralizing TK-antibody. This study demonstrates a novel role of TK in skin wound healing and uncovers new signaling pathways mediated by TK in promoting keratinocyte migration through activation of the PAR1-PKC-Src-MMP pathway and HB-EGF/AR shedding-dependent EGFR transactivation.
登录
查看更多内容
影响因子：
4.8
作者：
Koon, HW;Zhao, DZ;Pothoulakis, C
通讯作者：
Pothoulakis, C
DOI：
10.2174/1568016052773351
发表时间：
2005-01-05
期刊：
Current Medicinal Chemistry - Cardiovascular & Hematological Agents
影响因子：
--
作者：
Marcondes, S.;Antunes, E.
通讯作者：
Antunes, E.
DOI：
10.1016/j.jtcvs.2005.08.050
发表时间：
2006-01-01
影响因子：
6
作者：
Day, JRS;Taylor, KM;Landis, RC
通讯作者：
Landis, RC
影响因子：
4.3
作者：
Nichol, SM;Roztocil, E;Davies, MG
通讯作者：
Davies, MG
影响因子：
5.3
作者：
Huang, XZ;Griffiths, M;Sheppard, D
通讯作者：
Sheppard, D