Departments of Biochemistry and College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Korea.
BMB Rep. 2010 Feb;43(2):91-6. doi: 10.5483/bmbrep.2010.43.2.091.
The function of macrophage inhibitory cytokine-1 (MIC-1) in cancer remains controversial, and its signaling pathways remain poorly understood. In this study, we demonstrate that MIC-1 induces the transactivation of EGFR, ErbB2, and ErbB3 through the activation of c-Src in SK-BR-3 breast cells. MIC-1 induced significant phosphorylation of EGFR at Tyr845, ErbB2 at Tyr877, and ErbB3 at Tyr1289 as well as Akt and p38, Erk1/2, and JNK mitogen-activated protein kinases (MAPKs). Treatment of SK-BR-3 cells with MIC-1 increased the phosphorylation level of Src at Tyr416, and induced invasiveness of those cells. Inhibition of c-Src activity resulted in the complete abolition of MIC-1-induced phosphorylation of the EGFR, ErbB2, and ErbB3, as well as invasiveness and matrix metalloproteinase (MMP)-9 expression in SK-BR-3 cells. Collectively, these results show that MIC-1 may participate in the malignant progression of certain cancer cells through the activation of c-Src, which in turn may transactivate ErbB-family receptors.
巨噬细胞抑制细胞因子-1（MIC-1）在癌症中的功能仍存在争议，其信号通路也知之甚少。在这项研究中，我们证明 MIC-1 通过激活 SK-BR-3 乳腺癌细胞中的 c-Src 诱导 EGFR、ErbB2 和 ErbB3 的转激活。MIC-1 诱导 EGFR 在 Tyr845、ErbB2 在 Tyr877 和 ErbB3 在 Tyr1289 以及 Akt 和 p38、Erk1/2 和 JNK 丝裂原激活蛋白激酶（MAPKs）的显著磷酸化。用 MIC-1 处理 SK-BR-3 细胞可增加 Src 在 Tyr416 处的磷酸化水平，并诱导这些细胞的侵袭性。抑制 c-Src 活性可导致 MIC-1 诱导的 EGFR、ErbB2 和 ErbB3 的磷酸化以及 SK-BR-3 细胞的侵袭性和基质金属蛋白酶（MMP）-9 表达完全消除。总之，这些结果表明 MIC-1 可能通过激活 c-Src 参与某些癌细胞的恶性进展，而 c-Src 又可能转激活 ErbB 家族受体。
