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

8 Citations (Scopus)

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

Fingerprint

Glioblastoma
Epidermal Growth Factor
Cell Movement
Neoplasms
MAP Kinase Kinase Kinases
Guanine Nucleotide Exchange Factors
mitogen-activated protein kinase kinase kinase 11
Recurrence
Brain

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

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

EGFR signals through a DOCK180-MLK3 axis to drive glioblastoma cell invasion. / Misek, Sean A.; Chen, Jian; Schroeder, Laura; Rattanasinchai, Chotirat; Sample, Ashley; Sarkaria, Jann N; Gallo, Kathleen A.

In: Molecular Cancer Research, Vol. 15, No. 8, 01.08.2017, p. 1085-1095.

Research output: Contribution to journalArticle

Misek, SA, Chen, J, Schroeder, L, Rattanasinchai, C, Sample, A, Sarkaria, JN & Gallo, KA 2017, 'EGFR signals through a DOCK180-MLK3 axis to drive glioblastoma cell invasion', Molecular Cancer Research, vol. 15, no. 8, pp. 1085-1095. https://doi.org/10.1158/1541-7786.MCR-16-0318
Misek, Sean A. ; Chen, Jian ; Schroeder, Laura ; Rattanasinchai, Chotirat ; Sample, Ashley ; Sarkaria, Jann N ; Gallo, Kathleen A. / EGFR signals through a DOCK180-MLK3 axis to drive glioblastoma cell invasion. In: Molecular Cancer Research. 2017 ; Vol. 15, No. 8. pp. 1085-1095.
@article{f10ff23f8a6349de9713059549baf5af,
title = "EGFR signals through a DOCK180-MLK3 axis to drive glioblastoma cell invasion",
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.",
author = "Misek, {Sean A.} and Jian Chen and Laura Schroeder and Chotirat Rattanasinchai and Ashley Sample and Sarkaria, {Jann N} and Gallo, {Kathleen A.}",
year = "2017",
month = "8",
day = "1",
doi = "10.1158/1541-7786.MCR-16-0318",
language = "English (US)",
volume = "15",
pages = "1085--1095",
journal = "Molecular Cancer Research",
issn = "1541-7786",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - EGFR signals through a DOCK180-MLK3 axis to drive glioblastoma cell invasion

AU - Misek, Sean A.

AU - Chen, Jian

AU - Schroeder, Laura

AU - Rattanasinchai, Chotirat

AU - Sample, Ashley

AU - Sarkaria, Jann N

AU - Gallo, Kathleen A.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85026644661&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85026644661&partnerID=8YFLogxK

U2 - 10.1158/1541-7786.MCR-16-0318

DO - 10.1158/1541-7786.MCR-16-0318

M3 - Article

VL - 15

SP - 1085

EP - 1095

JO - Molecular Cancer Research

JF - Molecular Cancer Research

SN - 1541-7786

IS - 8

ER -