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 9

ERK3 is highly upregulated in human lung carcinomas.

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ERK3 is highly upregulated in human lung carcinomas. (A) ERK3 gene expre...
(A) ERK3 gene expression is highly upregulated in squamous cell lung carcinomas compared with that in normal lung tissues. ERK3 gene expression in squamous cell lung carcinomas (n = 21) and normal lung samples (n = 17) was analyzed on Affimetrix U95A microarrays (14). The P value was calculated using unpaired 2-tailed t test. Horizontal bars indicate the median; boxes indicate 25th to 75th percentiles; and whiskers indicate 10th and 90th percentiles. (B) Immunohistological analysis of ERK3 protein expression in an NSCLC TMA that contains 302 lung adenocarcinomas and 154 squamous cell lung carcinomas. Statistical significance was determined by unpaired 2-tailed t test.