title: 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.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Weiwen
authors.initials: W
authors.lastname: Long
authors.forename: Charles E
authors.initials: CE
authors.lastname: Foulds
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Chen
authors.initials: C
authors.lastname: Ding
authors.forename: David M
authors.initials: DM
authors.lastname: Lonard
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Solis
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.forename: Sophia Y
authors.initials: SY
authors.lastname: Tsai
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tsai
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D048053:Mitogen-Activated Protein Kinase 6 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D056921:Nuclear Receptor Coactivator 3 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors; C065788:transcription factor PEA3; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; D048053:Mitogen-Activated Protein Kinase 6; D020782:Matrix Metalloproteinases