EGFRvIII stimulates glioma growth and invasion through PKA-dependent serine phosphorylation of Dock180

H. Feng, B. Hu*, K. Vuori, J. N. Sarkaria, F. B. Furnari, W. K. Cavenee, S. Y. Cheng

*Corresponding author for this work

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Glioblastomas (GBMs), the most common and malignant brain tumors, are highly resistant to current therapies. The failure of targeted therapies against aberrantly activated oncogenic signaling, such as that of the EGFR-PI3K/Akt pathway, underscores the urgent need to understand alternative downstream pathways and to identify new molecular targets for the development of more effective treatments for gliomas. Here, we report that EGFRvIII (ΔEGFR/de2-7EGFR), a constitutively active EGFR mutant that is frequently co-overexpressed with EGFR in clinical GBM tumors, promotes glioma growth and invasion through protein kinase A (PKA)-dependent phosphorylation of Dock180, a bipartite guanine nucleotide exchange factor (GEF) for Rac1. We demonstrate that EGFRvIII induces serine phosphorylation of Dock180, stimulates Rac1 activation and glioma cell migration. Treatments of glioma cells using the PKA inhibitors H-89 and KT5720, overexpression of a PKA inhibitor (PKI), and in vitro PKA kinase assays show that EGFRvIII induction of serine phosphorylation of Dock180 is PKA-dependent. Significantly, PKA induces phosphorylation of Dock180 at amino acid residue S1250 that resides within its Rac1-activating DHR-2 domain. Expression of the Dock180 S1250L mutant, but not wild type Dock180 WT, protein in EGFRvIII-expressing glioma cells inhibited receptor-stimulated cell proliferation, survival, migration in vitro and glioma tumor growth and invasion in vivo. Together, our findings describe a novel mechanism by which EGFRvIII drives glioma tumorigenesis and invasion through PKA-dependent phosphorylation of Dock180, thereby suggesting that targeting EGFRvIII-PKA-Dock180-Rac1 signaling axis could provide a novel pathway to develop potential therapeutic strategies for malignant gliomas.

Original languageEnglish (US)
Pages (from-to)2504-2512
Number of pages9
JournalOncogene
Volume33
Issue number19
DOIs
StatePublished - May 8 2014

Fingerprint

Cyclic AMP-Dependent Protein Kinases
Glioma
Serine
Phosphorylation
Growth
Glioblastoma
Protein Kinase Inhibitors
PDZ Domains
Guanine Nucleotide Exchange Factors
epidermal growth factor receptor VIII
Phosphatidylinositol 3-Kinases
Brain Neoplasms
Cell Movement
Neoplasms
Cell Survival
Carcinogenesis
Phosphotransferases
Therapeutics
Cell Proliferation
Amino Acids

Keywords

  • Dock180
  • EGFRvIII
  • PKA
  • glioblastomas
  • phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Feng, H. ; Hu, B. ; Vuori, K. ; Sarkaria, J. N. ; Furnari, F. B. ; Cavenee, W. K. ; Cheng, S. Y. / EGFRvIII stimulates glioma growth and invasion through PKA-dependent serine phosphorylation of Dock180. In: Oncogene. 2014 ; Vol. 33, No. 19. pp. 2504-2512.
@article{f94e7dc5474145589e279dbf070e27ff,
title = "EGFRvIII stimulates glioma growth and invasion through PKA-dependent serine phosphorylation of Dock180",
abstract = "Glioblastomas (GBMs), the most common and malignant brain tumors, are highly resistant to current therapies. The failure of targeted therapies against aberrantly activated oncogenic signaling, such as that of the EGFR-PI3K/Akt pathway, underscores the urgent need to understand alternative downstream pathways and to identify new molecular targets for the development of more effective treatments for gliomas. Here, we report that EGFRvIII (ΔEGFR/de2-7EGFR), a constitutively active EGFR mutant that is frequently co-overexpressed with EGFR in clinical GBM tumors, promotes glioma growth and invasion through protein kinase A (PKA)-dependent phosphorylation of Dock180, a bipartite guanine nucleotide exchange factor (GEF) for Rac1. We demonstrate that EGFRvIII induces serine phosphorylation of Dock180, stimulates Rac1 activation and glioma cell migration. Treatments of glioma cells using the PKA inhibitors H-89 and KT5720, overexpression of a PKA inhibitor (PKI), and in vitro PKA kinase assays show that EGFRvIII induction of serine phosphorylation of Dock180 is PKA-dependent. Significantly, PKA induces phosphorylation of Dock180 at amino acid residue S1250 that resides within its Rac1-activating DHR-2 domain. Expression of the Dock180 S1250L mutant, but not wild type Dock180 WT, protein in EGFRvIII-expressing glioma cells inhibited receptor-stimulated cell proliferation, survival, migration in vitro and glioma tumor growth and invasion in vivo. Together, our findings describe a novel mechanism by which EGFRvIII drives glioma tumorigenesis and invasion through PKA-dependent phosphorylation of Dock180, thereby suggesting that targeting EGFRvIII-PKA-Dock180-Rac1 signaling axis could provide a novel pathway to develop potential therapeutic strategies for malignant gliomas.",
keywords = "Dock180, EGFRvIII, PKA, glioblastomas, phosphorylation",
author = "H. Feng and B. Hu and K. Vuori and Sarkaria, {J. N.} and Furnari, {F. B.} and Cavenee, {W. K.} and Cheng, {S. Y.}",
year = "2014",
month = "5",
day = "8",
doi = "10.1038/onc.2013.198",
language = "English (US)",
volume = "33",
pages = "2504--2512",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "19",

}

EGFRvIII stimulates glioma growth and invasion through PKA-dependent serine phosphorylation of Dock180. / Feng, H.; Hu, B.; Vuori, K.; Sarkaria, J. N.; Furnari, F. B.; Cavenee, W. K.; Cheng, S. Y.

In: Oncogene, Vol. 33, No. 19, 08.05.2014, p. 2504-2512.

Research output: Contribution to journalArticle

TY - JOUR

T1 - EGFRvIII stimulates glioma growth and invasion through PKA-dependent serine phosphorylation of Dock180

AU - Feng, H.

AU - Hu, B.

AU - Vuori, K.

AU - Sarkaria, J. N.

AU - Furnari, F. B.

AU - Cavenee, W. K.

AU - Cheng, S. Y.

PY - 2014/5/8

Y1 - 2014/5/8

N2 - Glioblastomas (GBMs), the most common and malignant brain tumors, are highly resistant to current therapies. The failure of targeted therapies against aberrantly activated oncogenic signaling, such as that of the EGFR-PI3K/Akt pathway, underscores the urgent need to understand alternative downstream pathways and to identify new molecular targets for the development of more effective treatments for gliomas. Here, we report that EGFRvIII (ΔEGFR/de2-7EGFR), a constitutively active EGFR mutant that is frequently co-overexpressed with EGFR in clinical GBM tumors, promotes glioma growth and invasion through protein kinase A (PKA)-dependent phosphorylation of Dock180, a bipartite guanine nucleotide exchange factor (GEF) for Rac1. We demonstrate that EGFRvIII induces serine phosphorylation of Dock180, stimulates Rac1 activation and glioma cell migration. Treatments of glioma cells using the PKA inhibitors H-89 and KT5720, overexpression of a PKA inhibitor (PKI), and in vitro PKA kinase assays show that EGFRvIII induction of serine phosphorylation of Dock180 is PKA-dependent. Significantly, PKA induces phosphorylation of Dock180 at amino acid residue S1250 that resides within its Rac1-activating DHR-2 domain. Expression of the Dock180 S1250L mutant, but not wild type Dock180 WT, protein in EGFRvIII-expressing glioma cells inhibited receptor-stimulated cell proliferation, survival, migration in vitro and glioma tumor growth and invasion in vivo. Together, our findings describe a novel mechanism by which EGFRvIII drives glioma tumorigenesis and invasion through PKA-dependent phosphorylation of Dock180, thereby suggesting that targeting EGFRvIII-PKA-Dock180-Rac1 signaling axis could provide a novel pathway to develop potential therapeutic strategies for malignant gliomas.

AB - Glioblastomas (GBMs), the most common and malignant brain tumors, are highly resistant to current therapies. The failure of targeted therapies against aberrantly activated oncogenic signaling, such as that of the EGFR-PI3K/Akt pathway, underscores the urgent need to understand alternative downstream pathways and to identify new molecular targets for the development of more effective treatments for gliomas. Here, we report that EGFRvIII (ΔEGFR/de2-7EGFR), a constitutively active EGFR mutant that is frequently co-overexpressed with EGFR in clinical GBM tumors, promotes glioma growth and invasion through protein kinase A (PKA)-dependent phosphorylation of Dock180, a bipartite guanine nucleotide exchange factor (GEF) for Rac1. We demonstrate that EGFRvIII induces serine phosphorylation of Dock180, stimulates Rac1 activation and glioma cell migration. Treatments of glioma cells using the PKA inhibitors H-89 and KT5720, overexpression of a PKA inhibitor (PKI), and in vitro PKA kinase assays show that EGFRvIII induction of serine phosphorylation of Dock180 is PKA-dependent. Significantly, PKA induces phosphorylation of Dock180 at amino acid residue S1250 that resides within its Rac1-activating DHR-2 domain. Expression of the Dock180 S1250L mutant, but not wild type Dock180 WT, protein in EGFRvIII-expressing glioma cells inhibited receptor-stimulated cell proliferation, survival, migration in vitro and glioma tumor growth and invasion in vivo. Together, our findings describe a novel mechanism by which EGFRvIII drives glioma tumorigenesis and invasion through PKA-dependent phosphorylation of Dock180, thereby suggesting that targeting EGFRvIII-PKA-Dock180-Rac1 signaling axis could provide a novel pathway to develop potential therapeutic strategies for malignant gliomas.

KW - Dock180

KW - EGFRvIII

KW - PKA

KW - glioblastomas

KW - phosphorylation

UR - http://www.scopus.com/inward/record.url?scp=84900390547&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84900390547&partnerID=8YFLogxK

U2 - 10.1038/onc.2013.198

DO - 10.1038/onc.2013.198

M3 - Article

C2 - 23728337

AN - SCOPUS:84900390547

VL - 33

SP - 2504

EP - 2512

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 19

ER -