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

Weiwen Long1, Charles E Foulds, Jun Qin

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.

The Journal of Clinical Investigation
|April 17, 2012
PubMed

Insights

Atypical MAPK ERK3 promotes lung cancer invasion by phosphorylating the oncogenic SRC-3 protein. This interaction enhances tumor cell invasiveness and tumor formation, highlighting ERK3 as a potential therapeutic target for lung cancer.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Atypical mitogen-activated protein kinase (MAPK) ERK3 signaling is poorly understood compared to classic MAPKs.
  • ERK3's role in cancer progression, particularly its substrates and regulation, remains largely unelucidated.
  • Steroid receptor coactivator 3 (SRC-3) is an oncogenic protein frequently overexpressed in human cancers.

Purpose of the Study:

  • To investigate the role of the atypical MAPK ERK3 in cancer progression.
  • To identify substrates and regulatory mechanisms of ERK3 signaling in the context of cancer.
  • To explore the potential of ERK3 as a therapeutic target for invasive cancers.

Main Methods:

  • Investigated the interaction between ERK3 and SRC-3 using co-immunoprecipitation assays.
  • Determined the site of SRC-3 phosphorylation by ERK3 using mass spectrometry (serine 857).
  • Assessed the functional consequences of ERK3-SRC-3 interaction on MMP gene expression and cell invasion.
  • Utilized knockdown experiments (siRNA) to evaluate the in vivo role of ERK3 and SRC-3 in lung cancer xenograft models.
  • Analyzed ERK3 expression levels in human lung carcinoma tissues.

Main Results:

  • ERK3 directly interacts with and phosphorylates the oncogenic protein SRC-3 at serine 857 (S857).
  • ERK3-mediated phosphorylation of SRC-3 at S857 is crucial for SRC-3 interaction with the transcription factor PEA3.
  • The SRC-3/PEA3 complex upregulates matrix metalloproteinase (MMP) gene expression, promoting lung cancer cell invasiveness.
  • Knockdown of ERK3 or SRC-3 significantly inhibits lung cancer cell invasion and tumor formation in vivo.
  • ERK3 is frequently upregulated in human lung carcinomas.

Conclusions:

  • The study identifies a novel signaling pathway where ERK3 promotes lung cancer cell invasiveness.
  • ERK3 phosphorylates SRC-3 at S857, enhancing its interaction with PEA3 and driving proinvasive gene expression.
  • ERK3 plays a critical role in lung cancer cell invasion and tumorigenesis.
  • ERK3 represents a promising therapeutic target for invasive lung cancers.

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