SHP-2-Erk signaling regulates concanavalin A-dependent production of TIMP-2
SHP-2-Erk signaling regulates concanavalin A-dependent production of TIMP-2
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DOI：
10.1016/j.bbrc.2006.07.173
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发表时间：
2006-09-29
影响因子：
3.1
通讯作者：
Hamaguchi, Michinari
中科院分区：
文献类型：
--
作者：
Biswas, Md. Helal Uddin;Hasegawa, Hitoki;Hamaguchi, Michinari
为了寻找组织金属蛋白酶-2 （TIMP-2）产生的关键信号，我们研究了SHP-2在刀豆蛋白A （Con A）处理的细胞中产生TIMP-2的作用。在野生型成纤维细胞中，Con - a处理显著激活了TIMP-2的产生。相比之下，在表达SHP-2突变体的细胞中，Con a处理导致TIMP-2的产生严重受损，因为SHP-2 - n结构域的65个氨基酸被删除。Con - a处理以依赖shp -2的方式激活双信号通路，Erk和p38。用MEK1的有效抑制剂U0126预处理野生型细胞，可以显著抑制TIMP-2的产生，而p38的特异性抑制剂SB203580则不能。最后，外源性野生型SHP-2在SHP-2突变细胞中的表达明显挽救了Erk的激活和TIMP-2的产生，以响应Con - a处理。综上所述，我们的研究结果强烈表明，SHP-2在成纤维细胞中通过MEK1-Erk信号传导产生TIMP-2的过程中起着重要的正向调节作用。(c) 2006爱思唯尔公司版权所有。
To search for the signaling critical for the production of tissue inhibitor of metalloprotemase-2 (TIMP-2), we investigated the role of SHP-2 in TIMP-2 production with Concanavalin A (Con A)-treated cells. In wild-type fibroblasts, Con A-treatment dramatically activated TIMP-2 production. In contrast, production of TIMP-2 in response to Con A-treatment was severely impaired in cells expressing mutant SHP-2 whose 65 amino acids in the SH2-N domain were deleted. Con A-treatment activated dual signaling pathways, Erk and p38, in a SHP-2-dependent manner. Pretreatment of wild-type cells with U0126, a potent inhibitor of MEK1, significantly inhibited the production of TIMP-2, whereas SB203580, a specific inhibitor for p38, could not. Finally, expression of exogenous wild-type SHP-2 in SHP-2 mutant cells clearly rescued Erk activation and TIMP-2 production in response to Con A-treatment. Taken together, our results strongly suggest that SHP-2 plays a critical role as a positive modulator for the production of TIMP-2 via MEK1-Erk signaling in fibroblasts. (c) 2006 Elsevier Inc. All rights reserved.