1. 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
- Author
-
Bertrand Perret, Carla Sampaio, Nicole Malet, Armelle Yart, Marie Dance, Jean-Pierre Salles, Patrick Raynal, Thomas Edouard, Alexandra Montagner, Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), and Université Toulouse - Jean Jaurès (UT2J)
- Subjects
Mitogen-Activated Protein Kinase 3 ,[SDV]Life Sciences [q-bio] ,Amino Acid Motifs ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Biology ,Gene Expression Regulation, Enzymologic ,Cell Line ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,Chlorocebus aethiops ,Animals ,Humans ,Epidermal growth factor receptor ,RNA, Small Interfering ,Protein Kinase Inhibitors ,Molecular Biology ,ComputingMilieux_MISCELLANEOUS ,Adaptor Proteins, Signal Transducing ,GRB2 Adaptor Protein ,Phosphoinositide-3 Kinase Inhibitors ,030304 developmental biology ,EGFR inhibitors ,Mitogen-Activated Protein Kinase 1 ,0303 health sciences ,Phosphoinositide 3-kinase ,Signal transducing adaptor protein ,Articles ,Cell Biology ,Cell biology ,Enzyme Activation ,ErbB Receptors ,030220 oncology & carcinogenesis ,ras Proteins ,Cancer research ,biology.protein ,GRB2 ,Signal transduction ,Signal Transduction - Abstract
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 PIP(3), 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 PIP(3) 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.
- Published
- 2008