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Molecular and Cellular Biology, January 2008, p. 587-600, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.01318-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Signal Strength Dictates Phosphoinositide 3-Kinase Contribution to Ras/Extracellular Signal-Regulated Kinase 1 and 2 Activation via Differential Gab1/Shp2 Recruitment: Consequences for Resistance to Epidermal Growth Factor Receptor Inhibition{triangledown} ,{dagger}

Carla Sampaio,1,{ddagger} Marie Dance,1,{ddagger} Alexandra Montagner,1 Thomas Edouard,1 Nicole Malet,1 Bertrand Perret,1,2 Armelle Yart,1 Jean-Pierre Salles,1,2 and Patrick Raynal1,2*

INSERM U563, Département Lipoprotéines et Médiateurs Lipidiques, Site Purpan, Toulouse F-31024, France,1 CHRU and Université Toulouse III, Hôpital Purpan, Toulouse F-31000, France2

Received 23 July 2007/ Returned for modification 21 August 2007/ Accepted 4 November 2007

Phosphoinositide 3-kinase (PI3K) participates in extracellular signal-regulated kinase 1 and 2 (ERK1-2) activation according to signal strength, through unknown mechanisms. We report herein that Gab1/Shp2 constitutes a PI3K-dependent checkpoint of ERK1-2 activation regulated according to signal intensity. Indeed, by up- and down-regulation of signal strength in different cell lines and through different methods, we observed that Gab1/Shp2 and Ras/ERK1-2 in concert become independent of PI3K upon strong epidermal growth factor receptor (EGFR) stimulation and dependent on PI3K upon limited EGFR activation. Using Gab1 mutants, we observed that this conditional role of PI3K is dictated by the EGFR capability of recruiting Gab1 through Grb2 or through the PI3K lipid product PIP3, according to a high or weak level of receptor stimulation, respectively. In agreement, Grb2 siRNA generates, in cells with maximal EGFR stimulation, a strong dependence on PI3K for both Gab1/Shp2 and ERK1-2 activation. Therefore, Ras/ERK1-2 depends on PI3K only when PIP3 is required to recruit Gab1/Shp2, which occurs only under weak EGFR mobilization. Finally, we show that, in glioblastoma cells displaying residual EGFR activation, this compensatory mechanism becomes necessary to efficiently activate ERK1-2, which could probably contribute to tumor resistance to EGFR inhibitors.

* Corresponding author. Mailing address: INSERM U563, Dept. Lipoprotéines et Médiateurs Lipidiques, Site Purpan, BP3028, Toulouse F-31024, France. Phone: 33-562-748-671. Fax: 33-562-748-666. E-mail: raynal{at}toulouse.inserm.fr

{triangledown} Published ahead of print on 19 November 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally to the work.

Molecular and Cellular Biology, January 2008, p. 587-600, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.01318-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Rodland, K. D., Bollinger, N., Ippolito, D., Opresko, L. K., Coffey, R. J., Zangar, R., Wiley, H. S. (2008). Multiple Mechanisms Are Responsible for Transactivation of the Epidermal Growth Factor Receptor in Mammary Epithelial Cells. J. Biol. Chem. 283: 31477-31487 [Abstract] [Full Text]  


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