Ferritin blocks inhibitory effects of two-chain high molecular weight kininogen (HKa) on adhesion and survival signaling in endothelial cells.
Ferritin blocks inhibitory effects of two-chain high molecular weight kininogen (HKa) on adhesion and survival signaling in endothelial cells.
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DOI：
10.1371/journal.pone.0040030
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Torti SV
中科院分区：
文献类型：
--
作者：
Tesfay L;Huhn AJ;Hatcher H;Torti FM;Torti SV
血管生成通过促血管生成信号和抗血管生成信号之间的复杂串扰而受到严格调节。高分子量激肽原（HK）是一种内源性蛋白质，其在血浆中和内皮细胞表面上被蛋白水解切割成HKa（一种抗血管生成蛋白）。铁蛋白与HKa结合并阻断其抗血管生成活性。在这里，我们探讨铁蛋白的细胞保护作用的机制，在内皮细胞暴露于HKA。我们观察到铁蛋白促进HKa处理的细胞的粘附和存活，并恢复由Erk、Akt、FAK和桩蛋白介导的关键存活和粘附信号通路。我们进一步阐明了对内皮细胞的影响所需的HKa和铁蛋白的结构基序。我们确定了一个组氨酸-甘氨酸-赖氨酸（HGK）丰富的抗增殖区域内的域5 HK作为铁蛋白的目标，并证明了铁蛋白亚基的H和L型调节HKA活性。我们进一步证明铁蛋白减少了HKa与内皮细胞的结合，并恢复了uPAR与α5β1整联蛋白的结合。我们认为铁蛋白通过减少HKA与UPAR的结合并干扰HKA的抗粘附和抗增殖信号传导来阻断HKA的抗血管生成活性。
Angiogenesis is tightly regulated through complex crosstalk between pro- and anti-angiogenic signals. High molecular weight kininogen (HK) is an endogenous protein that is proteolytically cleaved in plasma and on endothelial cell surfaces to HKa, an anti-angiogenic protein. Ferritin binds to HKa and blocks its anti-angiogenic activity. Here, we explore mechanisms underlying the cytoprotective effect of ferritin in endothelial cells exposed to HKa. We observe that ferritin promotes adhesion and survival of HKa-treated cells and restores key survival and adhesion signaling pathways mediated by Erk, Akt, FAK and paxillin. We further elucidate structural motifs of both HKa and ferritin that are required for effects on endothelial cells. We identify an histidine-glycine-lysine (HGK) -rich antiproliferative region within domain 5 of HK as the target of ferritin, and demonstrate that both ferritin subunits of the H and L type regulate HKa activity. We further demonstrate that ferritin reduces binding of HKa to endothelial cells and restores the association of uPAR with α5β1 integrin. We propose that ferritin blocks the anti-angiogenic activity of HKa by reducing binding of HKa to UPAR and interfering with anti-adhesive and anti-proliferative signaling of HKa.
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DOI：
10.1083/jcb.200304105
发表时间：
2003-09-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hood JD;Frausto R;Kiosses WB;Schwartz MA;Cheresh DA
通讯作者：
Cheresh DA
影响因子：
11.8
作者：
Li, Jau Yi;Paragas, Neal;Ned, Renee M.;Qiu, Andong;Viltard, Melanie;Leete, Thomas;Drexler, Ian R.;Chen, Xia;Sanna-Cherchi, Simone;Mohammed, Farah;Williams, David;Lin, Chyuan Sheng;Schmidt-Ott, Kai M.;Andrews, Nancy C.;Barasch, Jonathan
通讯作者：
Barasch, Jonathan
影响因子：
20.3
作者：
Cohen, Lyora A.;Gutierrez, Lucia;Meyron-Holtz, Esther G.
通讯作者：
Meyron-Holtz, Esther G.
影响因子：
4
作者：
Guo, YL;Wang, SJ;Colman, RW
通讯作者：
Colman, RW
影响因子：
20.1
作者：
Cao, DJ;Guo, YL;Colman, RW
通讯作者：
Colman, RW