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Molecular and Cellular Biology, August 2003, p. 5803-5815, Vol. 23, No. 16
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.16.5803-5815.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Stimulation of Cell Proliferation by Endosomal Epidermal Growth Factor Receptor As Revealed through Two Distinct Phases of Signaling

Steven Pennock and Zhixiang Wang*

Department of Cell Biology and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

Received 31 January 2003/ Returned for modification 20 March 2003/ Accepted 9 May 2003

Strong evidence indicates that endosome-localized epidermal growth factor receptor (EGFR) plays an important role in cell signaling. However, elimination of endosomal signaling does not attenuate EGF-induced physiological outcomes, arguing against physiological relevance. Recently we established a system to specifically activate endosome-associated EGFR in the absence of any plasma membrane activation of EGFR and showed that endosomal EGFR signaling is sufficient to support cell survival. However, this pure endosomal signaling of EGFR does not stimulate cell proliferation, because EGFR only remained activated for less than 2 h following its stimulation at endosomes, while DNA synthesis generally requires growth factor exposure for 8 h or more. Here we report that the prolonged requirement for EGF to stimulate epithelial cell proliferation can be substituted for with two short pulses of EGF. By combining the two short pulses of EGF stimulation with our previously established method to generate endosomal EGFR signaling, we are able to generate two pulses of endosomal EGFR signaling. In this way, we demonstrated that two pulses of endosomal EGFR signaling are sufficient to stimulate cell proliferation. The first pulse of EGFR signaling induces exit from quiescence into G1 phase and appears to render cells responsive to subsequent mitogenic stimulus. This second pulse, required several hours later, drives cells through the restriction point of late G1 and into S phase. We further showed that the two pulses of endosomal EGFR signaling engaged cell cycle machinery the same way as the two pulses of standard EGFR signaling. Moreover, two pulses of endosomal EGFR signaling stimulated downstream signaling cascades in a similar way to the two pulses of standard EGFR activation. The data therefore demonstrate that signals transduced from internalized EGFR, with or without a contribution from the plasma membrane, fully satisfy the physiological requirements for S-phase entry.

* Corresponding author. Mailing address: Department of Cell Biology and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada. Phone: (780) 492-0710. Fax: (780) 492-0450. E-mail: zwang{at}cellbnt.ualberta.ca.

Molecular and Cellular Biology, August 2003, p. 5803-5815, Vol. 23, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.16.5803-5815.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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