Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China.
Hepatology. 2013 Jan;57(1):140-51. doi: 10.1002/hep.25978.
c-Jun N-terminal protein kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) superfamily. The activation of JNK is mediated by sequential protein phosphorylation through a MAPK module, namely, MAPK kinase kinase (MAP3K or MEKK) → MAPK kinase (MAP2K or MKK) → MAPK. Elevated levels of JNK activity have been frequently observed in hepatocellular carcinoma (HCC) and have been demonstrated to contribute to HCC growth by promoting HCC cell proliferation and resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)- or Fas-mediated apoptosis. Chronic inflammation contributes to the up-regulation of JNK activity in HCC. However, it remains unknown whether aberrant JNK activity also results from some cell intrinsic defect(s). Here, we show that receptor for activated C kinase 1 (RACK1), an adaptor protein implicated in the regulation of multiple signaling pathways, could engage in a direct interaction with MKK7, the JNK-specific MAP2K, in human HCC cells. Levels of RACK1 protein show correlation with the activity of the JNK pathway in human HCC tissues and cell lines. RACK1 loss-of-function or gain-of-function analyses indicate that RACK1 enhances MKK7/JNK activity in human HCC cells. Further exploration reveals that the interaction of RACK1 with MKK7 is required for the enhancement of MKK7/JNK activity by RACK1. RACK1/MKK7 interaction facilitates the association of MKK7 with MAP3Ks, thereby enhancing MKK7 activity and promoting in vitro HCC cell proliferation and resistance to TRAIL- or Fas-mediated apoptosis as well as in vivo tumor growth.
Overexpressed RACK1 augments JNK activity and thereby promotes HCC growth through directly binding to MKK7 and enhancing MKK7 activity.
c-Jun N-末端蛋白激酶（JNK）是丝裂原活化蛋白激酶（MAPK）超家族的成员。JNK 的激活是通过 MAPK 模块中的顺序蛋白磷酸化介导的，即 MAPK 激酶激酶（MAP3K 或 MEKK）→MAPK 激酶（MAP2K 或 MKK）→MAPK。JNK 活性水平升高在肝细胞癌（HCC）中经常观察到，并通过促进 HCC 细胞增殖和对肿瘤坏死因子相关凋亡诱导配体（TRAIL）或 Fas 介导的凋亡的抗性来证明对 HCC 生长有贡献。慢性炎症导致 HCC 中 JNK 活性的上调。然而，尚不清楚异常的 JNK 活性是否也来自某些细胞内在缺陷。在这里，我们表明，激活的 C 激酶 1 受体（RACK1），一种参与多种信号通路调节的衔接蛋白，可与人 HCC 细胞中的 JNK 特异性 MAP2K，MKK7 直接相互作用。RACK1 蛋白水平与人 HCC 组织和细胞系中的 JNK 途径活性相关。RACK1 功能丧失或获得功能分析表明，RACK1 增强了人 HCC 细胞中的 MKK7/JNK 活性。进一步探索表明，RACK1 与 MKK7 的相互作用是 RACK1 增强 MKK7/JNK 活性所必需的。RACK1/MKK7 相互作用促进 MKK7 与 MAP3Ks 的结合，从而增强 MKK7 活性，促进体外 HCC 细胞增殖和对 TRAIL 或 Fas 介导的凋亡的抗性以及体内肿瘤生长。
过表达的 RACK1 通过直接与 MKK7 结合并增强 MKK7 活性来增强 JNK 活性，从而促进 HCC 生长。
