EGFR signals through a DOCK180-MLK3 axis to drive glioblastoma cell invasion

Sean A. Misek, Jian Chen, Laura Schroeder, Chotirat Rattanasinchai, Ashley Sample, Jann N Sarkaria, Kathleen A. Gallo

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

A hallmark of glioblastoma (GBM) tumors is their highly invasive behavior. Tumor dissemination into surrounding brain tissue is responsible for incomplete surgical resection, and subsequent tumor recurrence. Identification of targets that control GBM cell dissemination is critical for developing effective therapies to treat GBM. A majority of GBM tumors have dysregulated EGFR signaling, due most frequently to EGFR amplification or the presence of a constitutively active EGFRvIII mutant. Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that can activate multiple MAPK pathways. In this study, evidence is provided that MLK3 is essential for GBM cell migration and invasion, and that an MLK inhibitor blocks EGF-induced migration and invasion. MLK3 silencing or MLK inhibition blocks EGF-induced JNK activation, suggesting that MLK3-JNK signaling promotes invasion of GBM cells. Mechanistically, it is demonstrated that DOCK180, a RAC1 guanine nucleotide exchange factor (GEF) overexpressed in invasive GBM cells, activates the MLK3-JNK signaling axis in a RAC1-dependent manner. In summary, this investigation identifies an EGFR-DOCK180-RAC1-MLK3-JNK signaling axis that drives glioblastoma cell migration and dissemination.

Original languageEnglish (US)
Pages (from-to)1085-1095
Number of pages11
JournalMolecular Cancer Research
Volume15
Issue number8
DOIs
StatePublished - Aug 1 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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    Misek, S. A., Chen, J., Schroeder, L., Rattanasinchai, C., Sample, A., Sarkaria, J. N., & Gallo, K. A. (2017). EGFR signals through a DOCK180-MLK3 axis to drive glioblastoma cell invasion. Molecular Cancer Research, 15(8), 1085-1095. https://doi.org/10.1158/1541-7786.MCR-16-0318