ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion
Weiwen Long, Charles E. Foulds, Jun Qin, Jian Liu, Chen Ding, David M. Lonard, Luisa M. Solis, Ignacio I. Wistuba, Jun Qin, Sophia Y. Tsai, Ming-Jer Tsai, Bert W. O’Malley
Weiwen Long, Charles E. Foulds, Jun Qin, Jian Liu, Chen Ding, David M. Lonard, Luisa M. Solis, Ignacio I. Wistuba, Jun Qin, Sophia Y. Tsai, Ming-Jer Tsai, Bert W. O’Malley
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Research Article Oncology

ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion

Abstract

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.

Authors

Weiwen Long, Charles E. Foulds, Jun Qin, Jian Liu, Chen Ding, David M. Lonard, Luisa M. Solis, Ignacio I. Wistuba, Jun Qin, Sophia Y. Tsai, Ming-Jer Tsai, Bert W. O’Malley

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Figure 8

Both SRC-3 and ERK3 are important for the invasiveness of H1299 lung cancer cells in vivo.

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Both SRC-3 and ERK3 are important for the invasiveness of H1299 lung can...
1 × 106 GFP-labeled H1299 cells with stable expression of the control shRNA (shCtrl), SRC-3 shRNA (shSRC-3), ERK3 shRNA (shERK3), or both shSRC3 and shERK3 were injected into SCID/Beige mice via tail vein. Five weeks after inoculation, formation of tumor nodules in the lungs was analyzed by GFP imaging of (A) the excised lungs or (B) frozen sections. Images shown in A are overlays of GFP-fluorescent images, with the corresponding white-light counterparts. The color scale bar at the right indicates GFP fluorescence intensity of the tumor nodules. Original magnification, ×50 (B). (C) The number of tumor nodules and foci in lungs was counted on the basis of GFP imaging. Values represent the mean ± SEM of 15 mice. *P < 0.05, **P < 0.001 (Student’s t test).