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首页> 外文期刊>Signal transduction: Receptors, mediators and genes: Official journal of the Signal Transduction Society >Concentration-dependent stimulation by tissue inhibitor of metalloproteinases(TIMP)-2 of two signaling pathways in human osteosarcoma (MG-63) Cells
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Concentration-dependent stimulation by tissue inhibitor of metalloproteinases(TIMP)-2 of two signaling pathways in human osteosarcoma (MG-63) Cells

机译：金属蛋白酶（TIMP）-2的组织抑制剂对人骨肉瘤（MG-63）细胞中两个信号通路的浓度依赖性刺激

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We reported previously that tyrosine kinase (TYK) and mitogen-activated protein kinase (MAPK) play a role in TIMP-dependent growth signaling. Here we demonstrate that the activation of MAPK stimulated by TIMP-2 was sharply inhibited in MG-63 cells by PP1, a selective inhibitor of Src-family tyrosine kinases, suggesting that Src activation is possibly required for the MAPK activity in response to 1 ng/mL TIMP-2. A specific cell-permeable inhibitor of MAPK kinase (MEK), PD 98058 had an inhibitory effect on MAPK activity, indicating that MEK is an upstream effector of MAPK. By transfecting MG-63 cells with dominant-negative Ras, RasN17, and furthermore, by using a selective farnesyltransferase inhibitor, FTI-277, we found that MAPK activation stimulated by TIMP-2 was independent of Ras. We also demonstrated that the activation of MAPK in response to 1 ng/mL TIMP-2 was inhibited by a cAMP agonist, 8-bromo-cAMP. On the contrary, [3H]thymidine incorporation and the activation of MAPK, all of which were heavily suppressed by increasing the TIMP-2 concentration up to 100 ng/mL, were recovered by the addition of a cell-permeable specific PKA inhibitor, H-89. These results strongly suggest the presence of a negative crosstalk from the cAMP/PKA pathway to the TYK/MAPK one.
机译：我们以前曾报道酪氨酸激酶（TYK）和丝裂原激活的蛋白激酶（MAPK）在TIMP依赖的生长信号中发挥作用。在这里，我们证明了PP1（一种Src家族酪氨酸激酶的选择性抑制剂）对TIM--2刺激的MAPK的激活在MG-63细胞中受到了明显的抑制，这表明MAPK活性可能需要Src激活才能响应1 ng。 / mL TIMP-2。 MAPK激酶（MEK）的一种特定的细胞可渗透抑制剂PD 98058对MAPK活性具有抑制作用，表明MEK是MAPK的上游效应物。通过用显性阴性Ras RasN17转染MG-63细胞，此外，通过使用选择性法呢基转移酶抑制剂FTI-277，我们发现TIMP-2刺激的MAPK激活独立于Ras。我们还证明了cAMP激动剂8-溴-cAMP抑制了响应1 ng / mL TIMP-2的MAPK激活。相反，[3H]胸腺嘧啶核苷的掺入和MAPK的激活通过添加可渗透细胞的特异性PKA抑制剂H得以恢复，而所有这些都通过将TIMP-2浓度提高至100 ng / mL而受到严重抑制。 -89。这些结果强烈表明从cAMP / PKA途径到TYK / MAPK途径存在负串扰。

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