Phosphorylation of dedicator of cytokinesis 1 (Dock180) at tyrosine residue Y722 by Src family kinases mediates EGFRvIII-driven glioblastoma tumorigenesis

Haizhong Feng, Bo Hu*, Michael J. Jarzynka, Yanxin Li, Susan Keezer, Terrance G. Johns, Careen K. Tang, Ronald L. Hamilton, Kristiina Vuori, Ryo Nishikawa, Jann N. Sarkaria, Tim Fenton, Tao Cheng, Frank B. Furnari, Webster K. Cavenee, Shi Yuan Cheng

*Corresponding author for this work

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Glioblastoma, the most common primary malignant cancer of the brain, is characterized by rapid tumor growth and infiltration of tumor cells throughout the brain. These traits cause glioblastomas to be highly resistant to current therapies with a resultant poor prognosis. Although aberrant oncogenic signaling driven by signature genetic alterations, such as EGF receptor (EGFR) gene amplification and mutation, plays a major role in glioblastoma pathogenesis, the responsible downstream mechanisms remain less clear. Here, we report that EGFRvIII (also known as ΔEGFR and de2-7EGFR), a constitutively active EGFR mutant that is frequently co-overexpressed with EGFR in human glioblastoma, promotes tumorigenesis through Src family kinase (SFK)-dependent phosphorylation of Dock180, a guanine nucleotide exchange factor for Rac1. EGFRvIII induces phosphorylation of Dock180 at tyrosine residue 722 (Dock180 Y722) and stimulates Rac1-signaling, glioblastoma cell survival and migration. Consistent with this being causal, siRNA knockdown of Dock180 or expression of a Dock180 Y722F mutant inhibits each of these EGFRvIII-stimulated activities. The SFKs, Src, Fyn, and Lyn, induce phosphorylation of Dock180 Y722 and inhibition of these SFKs by pharmacological inhibitors or shRNA depletion markedly attenuates EGFRvIII-induced phosphorylation of Dock180 Y722, Rac1 activity, and glioblastoma cell migration. Finally, phosphorylated Dock180 Y722 is coexpressed with EGFRvIII and phosphorylated Src Y418 in clinical specimens, and such coexpression correlates with an extremely poor survival in glioblastoma patients. These results suggest that targeting the SFK-p-Dock180 Y722-Rac1 signaling pathway may offer a novel therapeutic strategy for glioblastomas with EGFRvIII overexpression.

Original languageEnglish (US)
Pages (from-to)3018-3023
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number8
DOIs
StatePublished - Feb 21 2012

Fingerprint

Cytokinesis
src-Family Kinases
Glioblastoma
Tyrosine
Carcinogenesis
Phosphorylation
Epidermal Growth Factor Receptor
Small Interfering RNA
Cell Movement
Guanine Nucleotide Exchange Factors
epidermal growth factor receptor VIII
Gene Amplification
Brain Neoplasms
Neoplasms
Cell Survival
Pharmacology
Mutation
Survival
Brain
Therapeutics

Keywords

  • Akt
  • Invasion

ASJC Scopus subject areas

  • General

Cite this

Feng, Haizhong ; Hu, Bo ; Jarzynka, Michael J. ; Li, Yanxin ; Keezer, Susan ; Johns, Terrance G. ; Tang, Careen K. ; Hamilton, Ronald L. ; Vuori, Kristiina ; Nishikawa, Ryo ; Sarkaria, Jann N. ; Fenton, Tim ; Cheng, Tao ; Furnari, Frank B. ; Cavenee, Webster K. ; Cheng, Shi Yuan. / Phosphorylation of dedicator of cytokinesis 1 (Dock180) at tyrosine residue Y722 by Src family kinases mediates EGFRvIII-driven glioblastoma tumorigenesis. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 8. pp. 3018-3023.
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title = "Phosphorylation of dedicator of cytokinesis 1 (Dock180) at tyrosine residue Y722 by Src family kinases mediates EGFRvIII-driven glioblastoma tumorigenesis",
abstract = "Glioblastoma, the most common primary malignant cancer of the brain, is characterized by rapid tumor growth and infiltration of tumor cells throughout the brain. These traits cause glioblastomas to be highly resistant to current therapies with a resultant poor prognosis. Although aberrant oncogenic signaling driven by signature genetic alterations, such as EGF receptor (EGFR) gene amplification and mutation, plays a major role in glioblastoma pathogenesis, the responsible downstream mechanisms remain less clear. Here, we report that EGFRvIII (also known as ΔEGFR and de2-7EGFR), a constitutively active EGFR mutant that is frequently co-overexpressed with EGFR in human glioblastoma, promotes tumorigenesis through Src family kinase (SFK)-dependent phosphorylation of Dock180, a guanine nucleotide exchange factor for Rac1. EGFRvIII induces phosphorylation of Dock180 at tyrosine residue 722 (Dock180 Y722) and stimulates Rac1-signaling, glioblastoma cell survival and migration. Consistent with this being causal, siRNA knockdown of Dock180 or expression of a Dock180 Y722F mutant inhibits each of these EGFRvIII-stimulated activities. The SFKs, Src, Fyn, and Lyn, induce phosphorylation of Dock180 Y722 and inhibition of these SFKs by pharmacological inhibitors or shRNA depletion markedly attenuates EGFRvIII-induced phosphorylation of Dock180 Y722, Rac1 activity, and glioblastoma cell migration. Finally, phosphorylated Dock180 Y722 is coexpressed with EGFRvIII and phosphorylated Src Y418 in clinical specimens, and such coexpression correlates with an extremely poor survival in glioblastoma patients. These results suggest that targeting the SFK-p-Dock180 Y722-Rac1 signaling pathway may offer a novel therapeutic strategy for glioblastomas with EGFRvIII overexpression.",
keywords = "Akt, Invasion",
author = "Haizhong Feng and Bo Hu and Jarzynka, {Michael J.} and Yanxin Li and Susan Keezer and Johns, {Terrance G.} and Tang, {Careen K.} and Hamilton, {Ronald L.} and Kristiina Vuori and Ryo Nishikawa and Sarkaria, {Jann N.} and Tim Fenton and Tao Cheng and Furnari, {Frank B.} and Cavenee, {Webster K.} and Cheng, {Shi Yuan}",
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Feng, H, Hu, B, Jarzynka, MJ, Li, Y, Keezer, S, Johns, TG, Tang, CK, Hamilton, RL, Vuori, K, Nishikawa, R, Sarkaria, JN, Fenton, T, Cheng, T, Furnari, FB, Cavenee, WK & Cheng, SY 2012, 'Phosphorylation of dedicator of cytokinesis 1 (Dock180) at tyrosine residue Y722 by Src family kinases mediates EGFRvIII-driven glioblastoma tumorigenesis', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 8, pp. 3018-3023. https://doi.org/10.1073/pnas.1121457109

Phosphorylation of dedicator of cytokinesis 1 (Dock180) at tyrosine residue Y722 by Src family kinases mediates EGFRvIII-driven glioblastoma tumorigenesis. / Feng, Haizhong; Hu, Bo; Jarzynka, Michael J.; Li, Yanxin; Keezer, Susan; Johns, Terrance G.; Tang, Careen K.; Hamilton, Ronald L.; Vuori, Kristiina; Nishikawa, Ryo; Sarkaria, Jann N.; Fenton, Tim; Cheng, Tao; Furnari, Frank B.; Cavenee, Webster K.; Cheng, Shi Yuan.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 8, 21.02.2012, p. 3018-3023.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phosphorylation of dedicator of cytokinesis 1 (Dock180) at tyrosine residue Y722 by Src family kinases mediates EGFRvIII-driven glioblastoma tumorigenesis

AU - Feng, Haizhong

AU - Hu, Bo

AU - Jarzynka, Michael J.

AU - Li, Yanxin

AU - Keezer, Susan

AU - Johns, Terrance G.

AU - Tang, Careen K.

AU - Hamilton, Ronald L.

AU - Vuori, Kristiina

AU - Nishikawa, Ryo

AU - Sarkaria, Jann N.

AU - Fenton, Tim

AU - Cheng, Tao

AU - Furnari, Frank B.

AU - Cavenee, Webster K.

AU - Cheng, Shi Yuan

PY - 2012/2/21

Y1 - 2012/2/21

N2 - Glioblastoma, the most common primary malignant cancer of the brain, is characterized by rapid tumor growth and infiltration of tumor cells throughout the brain. These traits cause glioblastomas to be highly resistant to current therapies with a resultant poor prognosis. Although aberrant oncogenic signaling driven by signature genetic alterations, such as EGF receptor (EGFR) gene amplification and mutation, plays a major role in glioblastoma pathogenesis, the responsible downstream mechanisms remain less clear. Here, we report that EGFRvIII (also known as ΔEGFR and de2-7EGFR), a constitutively active EGFR mutant that is frequently co-overexpressed with EGFR in human glioblastoma, promotes tumorigenesis through Src family kinase (SFK)-dependent phosphorylation of Dock180, a guanine nucleotide exchange factor for Rac1. EGFRvIII induces phosphorylation of Dock180 at tyrosine residue 722 (Dock180 Y722) and stimulates Rac1-signaling, glioblastoma cell survival and migration. Consistent with this being causal, siRNA knockdown of Dock180 or expression of a Dock180 Y722F mutant inhibits each of these EGFRvIII-stimulated activities. The SFKs, Src, Fyn, and Lyn, induce phosphorylation of Dock180 Y722 and inhibition of these SFKs by pharmacological inhibitors or shRNA depletion markedly attenuates EGFRvIII-induced phosphorylation of Dock180 Y722, Rac1 activity, and glioblastoma cell migration. Finally, phosphorylated Dock180 Y722 is coexpressed with EGFRvIII and phosphorylated Src Y418 in clinical specimens, and such coexpression correlates with an extremely poor survival in glioblastoma patients. These results suggest that targeting the SFK-p-Dock180 Y722-Rac1 signaling pathway may offer a novel therapeutic strategy for glioblastomas with EGFRvIII overexpression.

AB - Glioblastoma, the most common primary malignant cancer of the brain, is characterized by rapid tumor growth and infiltration of tumor cells throughout the brain. These traits cause glioblastomas to be highly resistant to current therapies with a resultant poor prognosis. Although aberrant oncogenic signaling driven by signature genetic alterations, such as EGF receptor (EGFR) gene amplification and mutation, plays a major role in glioblastoma pathogenesis, the responsible downstream mechanisms remain less clear. Here, we report that EGFRvIII (also known as ΔEGFR and de2-7EGFR), a constitutively active EGFR mutant that is frequently co-overexpressed with EGFR in human glioblastoma, promotes tumorigenesis through Src family kinase (SFK)-dependent phosphorylation of Dock180, a guanine nucleotide exchange factor for Rac1. EGFRvIII induces phosphorylation of Dock180 at tyrosine residue 722 (Dock180 Y722) and stimulates Rac1-signaling, glioblastoma cell survival and migration. Consistent with this being causal, siRNA knockdown of Dock180 or expression of a Dock180 Y722F mutant inhibits each of these EGFRvIII-stimulated activities. The SFKs, Src, Fyn, and Lyn, induce phosphorylation of Dock180 Y722 and inhibition of these SFKs by pharmacological inhibitors or shRNA depletion markedly attenuates EGFRvIII-induced phosphorylation of Dock180 Y722, Rac1 activity, and glioblastoma cell migration. Finally, phosphorylated Dock180 Y722 is coexpressed with EGFRvIII and phosphorylated Src Y418 in clinical specimens, and such coexpression correlates with an extremely poor survival in glioblastoma patients. These results suggest that targeting the SFK-p-Dock180 Y722-Rac1 signaling pathway may offer a novel therapeutic strategy for glioblastomas with EGFRvIII overexpression.

KW - Akt

KW - Invasion

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