Kong Qingbin, Hua Hui, Cui Anguo, Shao Ting, Song Peiying, Jiang Yangfu
State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu 610041, China.
Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu 610041, China.
Int J Mol Sci. 2014 Sep 15;15(9):16246-56. doi: 10.3390/ijms150916246.
c-Jun N-terminal kinases (JNK) are members of the mitogen-activated protein kinase (MAPK) family that have important roles in signal transduction. The small molecule SP600125 is widely used in biochemical studies as a JNK inhibitor. However, recent studies indicate that SP600125 may also act independent of JNK. Here, we report that SP600125 can induce Src, type I insulin-like growth factor receptor (IGF-IR), Akt and Erk1/2 phosphorylation. Notably, these effects are independent of its inhibition of JNK. Inhibition of Src abrogates the stimulation of IGF-IR, Akt and Erk1/2 phosphorylation. IGF-IR knockdown blunts the induction of both Akt and Erk1/2 phosphorylation by SP600125. Moreover, combination of SP600125 and the Src inhibitor saracatinib synergistically inhibits cell proliferation. We conclude that SP600125 can activate Src-IGF-IR-Akt/Erk1/2 signaling pathways independent of JNK.
c-Jun氨基末端激酶（JNK）是丝裂原活化蛋白激酶（MAPK）家族的成员，在信号转导中起重要作用。小分子SP600125作为一种JNK抑制剂，在生化研究中被广泛使用。然而，最近的研究表明，SP600125也可能独立于JNK发挥作用。在此，我们报告SP600125可诱导Src、I型胰岛素样生长因子受体（IGF-IR）、Akt和Erk1/2磷酸化。值得注意的是，这些效应与其对JNK的抑制作用无关。抑制Src可消除对IGF-IR、Akt和Erk1/2磷酸化的刺激。敲低IGF-IR可减弱SP600125对Akt和Erk1/2磷酸化的诱导。此外，SP600125与Src抑制剂萨拉卡替尼联合使用可协同抑制细胞增殖。我们得出结论，SP600125可独立于JNK激活Src-IGF-IR-Akt/Erk1/2信号通路。
