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1 Department of Medicine, School of Medicine, CURE: Digestive Diseases Research Center and Molecular Biology Institute, University of California, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: erozengurt{at}mednet.ucla.edu.
The role of epidermal growth factor receptor (EGFR) tyrosine kinase and its downstream targets in the regulation of the transition from the G0/G1 phase into DNA synthesis in response to ANG II has not been previously investigated in intestinal epithelial IEC-18 cells. ANG II induced a rapid and striking EGFR tyrosine phosphorylation, which was prevented by selective inhibitors of EGFR tyrosine kinase activity (e.g. AG1478) or by broad-spectrum matrix metalloproteinase (MMP) inhibitor, GM 6001. Pretreatment of these cells with either AG1478 or GM 6001 reduced ANG II-stimulated DNA synthesis by ~50%. To elucidate the downstream targets of EGFR, we demonstrated that ANG II stimulated phosphorylation of Akt at Ser-473, mTOR at Ser-2448, p70S6K1 at Thr-389, and S6 ribosomal protein at Ser-235/236. Pretreatment with AG1478 inhibited Akt, p70S6K1, and S6 ribosomal protein phosphorylation. Inhibition of PI 3-kinase with LY 294002 or mTOR/p70S6K1 with rapamycin reduced [3H]-thymidine incorporation by 50%, i.e. to levels comparable to those achieved by addition of either AG1478 or GM 6001. Utilizing Akt siRNA targeted to Akt1 and Akt2, Akt protein knockdown dramatically inhibited p70S6K1 and S6 ribosomal protein phosphorylation. In contrast, AG1478 or Akt gene silencing exerted no detectable inhibitory effect on ANG II-induced ERK1/2 phosphorylation in IEC-18 cells. Taken together, our results demonstrate that EGFR transactivation mediates ANG II-stimulated mitogenesis through the PI 3-Kinase/Akt/mTOR/p70S6K1 signaling pathway in IEC-18 cells.
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