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
| Autor: | Bertrand Perret, Carla Sampaio, Nicole Malet, Armelle Yart, Marie Dance, Jean-Pierre Salles, Patrick Raynal, Thomas Edouard, Alexandra Montagner |
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| Přispěvatelé: | Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), Université Toulouse - Jean Jaurès (UT2J) |
| Rok vydání: | 2008 |
| Předmět: |
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 |
| Zdroj: | Molecular and Cellular Biology Molecular and Cellular Biology, American Society for Microbiology, 2008, 28 (2), pp.587-600. ⟨10.1128/MCB.01318-07⟩ |
| ISSN: | 1098-5549 0270-7306 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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