Convergence of Integrins and EGF Receptor Signaling Via PI3K/Akt/FoxO Pathway in Early Gene Egr-1 Expression

Year: 2009

Authors: Cabodi S., Morello V., Masi A., Cicchi R., Broggio C., Distefano P., Brunelli E., Silengo L., Pavone F.S., Arcangeli A., Turco E., Tarone G., Moro L., Defilippi P.

Autors Affiliation: Centro di Biotecnologie Molecolari and Dipartimento di Genetica, Biologia e Biochimica, Universita` di Torino, Torino, Italy; Dipartimento di Patologia ed Oncologia Sperimentali, Universita` di Firenze, Firenze, Italy; European Laboratory of non Linear Spectroscopy (LENS), Universita` di Firenze, Firenze, Italy; Dipartimento di Fisica, Universita` di Trento, Trento, Italy; Dipartimento Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Universita` del Piemonte Orientale, Novara, Italy; Dipartimento di Fisica, Universita` di Firenze, Firenze, Italy; Centro di Biotecnologie Molecolari and Dipartimento di Genetica, Biologia e Biochimica, Universita` di Torino, Torino, Italy

Abstract: The early gene early growth response (Egr-1), a broadly expressed member of the zing-finger family of transcription factors, is induced in many cell types by a variety of growth and differentiation stimuli, including epidermal growth factor (EGF). Here we demonstrate that Egr-1 expression is mainly regulated by integrin-mediated adhesion. Integrin-dependent adhesion plays a dual role in Egr-1 regulation, either being sufficient \”per se\” to induce Egr-1, or required for EGF-dependent expression of Egr-1, which occurs only in adherent cells and not in cells in suspension. To dissect the molecular basis of integrin-dependent Egr-1 regulation, we show by FLIM-based FRET that in living cells beta I-integrin associates with the EGF receptor (EGFR) and that EGF further increases the extent complex formation. Interestingly, Egr-1 induction depends on integrin-dependent PI3K/Akt activation, as indicated by the decrease in Egr-1 levels in presence of the pharmacological inhibitor LY294002, the kinase-defective Akt mutant and Akt1/2 shRNAs. Indeed, upon adhesion activated Akt translocates into the nucleus and phosphorylates FoxO1, a Forkhead transcription factors. Consistently, FoxO1 silencing results in Egr-1 increased levels, indicating that FoxO1 behaves as a negative regulator of Egr-1 expression. These data demonstrate that integrin/EGFR cross-talk is required for expression of Egr-1 through a novel regulatory cascade involving the activation of the PI3K/Akt/Forkhead pathway.


Volume: 218 (2)      Pages from: 294  to: 303

More Information: We thank Dr. E. Bergatto for initial experiments and Dr. Simona Degani for help with the confocal microscope. We also thank Dr. Piva for kindly provided the plasmids for Akt shRNAs. Alessio Masi is supported by the Association for International Cancer research (AICR). This work was supported by grants of the Italian Association for Cancer Research (AIRC), Association for International Cancer Research (AICR), EU FP7 program (Metafight), MUR (Ministero dell\’Universita e Ricerca Scientifica, cofinanziamento PRIN, fondi ex-60% and FIRB 200 1), Special project \”Oncology,\” Compagnia San Paolo/FIRM, Torino, Italy and Ente Cassa di Risparmio di Firenze, Progetto \”Promelab.\”
KeyWords: 2 morpholino 8 phenylchromone; beta1 integrin; early growth response factor 1; epidermal growth factor receptor; integrin; protein kinase B; transcription factor FOXO; beta1 integrin; epidermal growth factor; forkhead transcription factor; FOXO1 protein, human; phosphatidylinositol 3 kinase; unclassified drug, article; controlled study; enzyme activation; fluorescence resonance energy transfer; gene expression; human; human cell; priority journal; protein expression; protein phosphorylation; cell adhesion; cell line; cell membrane; cell nucleus; cell survival; drug effect; enzymology; genetic transcription; genetics; metabolism; phosphorylation; protein binding; protein transport; signal transduction, 1-Phosphatidylinositol 3-Kinase; Antigens, CD29; Cell Adhesion; Cell Line; Cell Membrane; Cell Nucleus; Cell Survival; Early Growth Response Protein 1; Enzyme Activation; Epidermal Growth Factor; Forkhead Transcription Factors; Humans; Phosphorylation; Protein Binding; Protein Transport; Proto-Oncogene Proteins c-akt; Receptor Cross-Talk; Receptor, Epidermal Growth Factor; Signal Transduction; Transcription, Genetic
DOI: 10.1002/jcp.21603

Citations: 54
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