PMID- 19176518
OWN - NLM
STAT- MEDLINE
DCOM- 20090318
LR  - 20211203
IS  - 1937-9145 (Electronic)
IS  - 1945-0877 (Linking)
VI  - 2
IP  - 55
DP  - 2009 Jan 27
TI  - EGFR signals to mTOR through PKC and independently of Akt in glioma.
PG  - ra4
LID - 10.1126/scisignal.2000014 [doi]
AB  - 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 phosphorylated mTOR (p-mTOR) and rpS6 
      (p-rpS6) in cells wild type for the gene encoding PTEN (phosphatase 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 
      PKCalpha as essential to this network, and question the necessity of Akt as a 
      critical intermediate coupling EGFR and mTOR in glioma.
FAU - Fan, Qi-Wen
AU  - Fan QW
AD  - Department of Neurology, University of California, 533 Parnassus Avenue, San 
      Francisco, CA 94143, USA.
FAU - Cheng, Christine
AU  - Cheng C
FAU - Knight, Zachary A
AU  - Knight ZA
FAU - Haas-Kogan, Daphne
AU  - Haas-Kogan D
FAU - Stokoe, David
AU  - Stokoe D
FAU - James, C David
AU  - James CD
FAU - McCormick, Frank
AU  - McCormick F
FAU - Shokat, Kevan M
AU  - Shokat KM
FAU - Weiss, William A
AU  - Weiss WA
LA  - eng
GR  - P50 CA097257/CA/NCI NIH HHS/United States
GR  - P50 CA097257-07/CA/NCI NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20090127
PL  - United States
TA  - Sci Signal
JT  - Science signaling
JID - 101465400
RN  - 0 (Enzyme Inhibitors)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.13 (Protein Kinase C)
SB  - IM
EIN - Sci Signal. 2009;2(60):er4
MH  - Brain Neoplasms/*metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Enzyme Inhibitors/pharmacology
MH  - ErbB Receptors/*metabolism
MH  - *Gene Expression Regulation, Neoplastic
MH  - Glioma/*metabolism
MH  - Humans
MH  - Models, Biological
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Protein Kinase C/*metabolism
MH  - Protein Kinases/*metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases
PMC - PMC2793677
MID - NIHMS91900
EDAT- 2009/01/30 09:00
MHDA- 2009/03/19 09:00
PMCR- 2009/12/15
CRDT- 2009/01/30 09:00
PHST- 2009/01/30 09:00 [entrez]
PHST- 2009/01/30 09:00 [pubmed]
PHST- 2009/03/19 09:00 [medline]
PHST- 2009/12/15 00:00 [pmc-release]
AID - 2/55/ra4 [pii]
AID - 10.1126/scisignal.2000014 [doi]
PST - epublish
SO  - Sci Signal. 2009 Jan 27;2(55):ra4. doi: 10.1126/scisignal.2000014.