Rapamycin induces transactivation of the EGFR and increases cell survival

D. Chaturvedi, X. Gao, Michael Cohen, J. Taunton, T. B. Patel

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

The mammalian target of rapamycin (mTOR) signaling network regulates cell growth, proliferation and cell survival. Deregulated activation of this pathway is a common event in diverse human diseases such as cancers, cardiac hypertrophy, vascular restenosis and nephrotic hypertrophy. Although mTOR inhibitor, rapamycin, has been widely used to inhibit the aberrant signaling due to mTOR activation that plays a major role in hyperproliferative diseases, in some cases rapamycin does not attenuate the cell proliferation and survival. Thus, we studied the mechanism(s) by which cells may confer resistance to rapamycin. Our data show that in a variety of cell types the mTOR inhibitor rapamycin activates extracellularly regulated kinases (Erk1/2) signaling. Rapamycin-mediated activation of the Erk1/2 signaling requires (a) the epidermal growth factor receptor (EGFR), (b) its tyrosine kinase activity and (c) intact autophosphorylation sites on the receptor. Rapamycin treatment increases tyrosine phosphorylation of EGFR without the addition of growth factor and this transactivation of receptor involves activation of c-Src. We also show that rapamycin treatment triggers activation of cell survival signaling pathway by activating the prosurvival kinases Erk1/2 and p90RSK. These studies provide a novel paradigm by which cells escape the apoptotic actions of rapamycin and its derivatives that inhibit the mTOR pathway.

Original languageEnglish (US)
Pages (from-to)1187-1196
Number of pages10
JournalOncogene
Volume28
Issue number9
DOIs
StatePublished - Mar 5 2009
Externally publishedYes

Fingerprint

Sirolimus
Epidermal Growth Factor Receptor
Transcriptional Activation
Cell Survival
Phosphotransferases
Cell Proliferation
Growth Factor Receptors
Cardiomegaly
Protein-Tyrosine Kinases
Hypertrophy
Blood Vessels
Tyrosine
Phosphorylation

Keywords

  • Apoptosis
  • c-Src
  • EGFR
  • mTOR
  • Rapamycin
  • Transactivation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Rapamycin induces transactivation of the EGFR and increases cell survival. / Chaturvedi, D.; Gao, X.; Cohen, Michael; Taunton, J.; Patel, T. B.

In: Oncogene, Vol. 28, No. 9, 05.03.2009, p. 1187-1196.

Research output: Contribution to journalArticle

Chaturvedi, D, Gao, X, Cohen, M, Taunton, J & Patel, TB 2009, 'Rapamycin induces transactivation of the EGFR and increases cell survival', Oncogene, vol. 28, no. 9, pp. 1187-1196. https://doi.org/10.1038/onc.2008.490
Chaturvedi, D. ; Gao, X. ; Cohen, Michael ; Taunton, J. ; Patel, T. B. / Rapamycin induces transactivation of the EGFR and increases cell survival. In: Oncogene. 2009 ; Vol. 28, No. 9. pp. 1187-1196.
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