ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion
ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion
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DOI：
10.1172/jci61492
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发表时间：
2012-05-01
影响因子：
15.9
通讯作者：
O'Malley, Bert W.
中科院分区：
文献类型：
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作者：
Long, Weiwen;Foulds, Charles E.;O'Malley, Bert W.
与经典的MAPK如ERK 1/2相比，对非典型MAPK ERK 3信号级联的调节和底物及其在癌症进展中的功能知之甚少。在这里，我们报告ERK 3相互作用和磷酸化类固醇受体辅激活因子3（SRC-3），一种致癌蛋白在多种人类癌症的丝氨酸857（S857）过度表达。这种ERK 3介导的S857磷酸化对于SRC-3与ETS转录因子PEA 3的相互作用至关重要，PEA 3促进肺癌细胞中MMP基因表达和促侵袭活性的上调。重要的是，在异种移植小鼠模型中，ERK 3或SRC-3的敲低抑制了肺癌细胞在肺中侵袭和形成肿瘤的能力。此外，发现ERK 3在人肺癌中高度上调。我们的研究确定了以前未知的作用ERK 3促进肺癌细胞的侵袭性磷酸化SRC-3和调节SRC-3的proinvasive活性的位点特异性磷酸化。因此，ERK 3蛋白激酶可能是浸润性肺癌治疗的一个有吸引力的靶点。
In contrast to the well-studied classic MAPKs, such as ERK1/2, little is known concerning the regulation and substrates of the atypical MAPK ERK3 signaling cascade and its function in cancer progression. Here, we report that ERK3 interacted with and phosphorylated steroid receptor coactivator 3 (SRC-3), an oncogenic protein overexpressed in multiple human cancers at serine 857 (S857). This ERK3-mediated phosphorylation at S857 was essential for interaction of SRC-3 with the ETS transcription factor PEA3, which promotes upregulation of MMP gene expression and proinvasive activity in lung cancer cells. Importantly, knockdown of ERK3 or SRC-3 inhibited the ability of lung cancer cells to invade and form tumors in the lung in a xenograft mouse model. In addition, ERK3 was found to be highly upregulated in human lung carcinomas. Our study identifies a previously unknown role for ERK3 in promoting lung cancer cell invasiveness by phosphorylating SRC-3 and regulating SRC-3 proinvasive activity by site-specific phosphorylation. As such, ERK3 protein kinase may be an attractive target for therapeutic treatment of invasive lung cancer.