EGFR signals to mTOR through PKC and independently of Akt in glioma

Qi Wen Fan, Christine Cheng, Zachary A. Knight, Daphne Haas-Kogan, David Stokoe, C. David James, Frank McCormick, Kevan M. Shokat, William A. Weiss

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

Amplification of the gene encoding the epidermal growth factor (EGF) receptor (EGFR) occurs commonly in glioblastoma, leading to activation of downstream kinases including phosphatidylinositol 3′-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). Here, we show that phosphorylation of mTOR and its downstream substrate rpS6 (ribosomal protein S6) are robust biomarkers for the antiproliferative effect of EGFR inhibitors. Inhibition of EGFR signaling correlated with decreased abundance of phos-phorylated mTOR (p-mTOR) and rpS6 (p-rpS6) in cells wild type for the gene encoding PTEN (phospha-tase and tensin homolog on chromosome 10), a negative regulator of PI3K. In contrast, inhibition of EGFR signaling failed to affect p-mTOR or p-rpS6 in cells mutant for PTEN, which are resistant to EGFR inhibitors. Although the abundance of phosphorylated Akt (p-Akt) decreased in response to inhibition of EGFR signaling, Akt was dispensable for signaling between EGFR and mTOR. We identified an Akt-independent pathway linking EGFR to mTOR that was critically dependent on protein kinase C (PKC). Consistent with these observations, the abundance of EGFR generally correlated with phosphorylation of rpS6 and PKC in primary human glioblastoma tumors, and correlated poorly with phosphorylation of Akt. Inhibition of PKC led to decreased viability of glioma cells regardless of PTEN or EGFR status, suggesting that PKC inhibitors should be tested in glioma. These findings underline the importance of signaling between EGFR and mTOR in glioma, identify PKCα as essential to this network, and question the necessity of Akt as a critical intermediate coupling EGFR and mTOR in glioma.

Original languageEnglish (US)
Pages (from-to)ra4
JournalScience Signaling
Volume2
Issue number55
DOIs
StatePublished - Jan 27 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Fan, Q. W., Cheng, C., Knight, Z. A., Haas-Kogan, D., Stokoe, D., James, C. D., McCormick, F., Shokat, K. M., & Weiss, W. A. (2009). EGFR signals to mTOR through PKC and independently of Akt in glioma. Science Signaling, 2(55), ra4. https://doi.org/10.1126/scisignal.2000014