Recent evidence indicates that integrin engagement results in the activation of biochemical signaling events important for regulating different cell functions, such as migration, adhesion, proliferation, differentiation, apoptosis, and specific gene expression. Here, we report that β1 integrin ligation on human natural killer (NK) cells results in the activation of Ras/mitogen-activated protein kinase pathways. Formation of Shc–growth factor receptor–bound protein 2 (Grb2) and Shc–proline-rich tyrosine kinase 2–Grb2 complexes are the receptor-proximal events accompanying the β1 integrin–mediated Ras activation. In addition, we demonstrate that ligation of β1 integrins results in the stimulation of interferon γ (IFN-γ) production, which is under the control of extracellular signal–regulated kinase 2 activation. Overall, our data indicate that β1 integrins, by delivering signals capable of triggering IFN-γ production, may function as NK-activating receptors.
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5 October 1998
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October 05 1998
Integrin-mediated Ras–Extracellular Regulated Kinase (ERK) Signaling Regulates Interferon γ Production in Human Natural Killer Cells
Fabrizio Mainiero,
Fabrizio Mainiero
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
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Angela Gismondi,
Angela Gismondi
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
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Alessandra Soriani,
Alessandra Soriani
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
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Marco Cippitelli,
Marco Cippitelli
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
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Gabriella Palmieri,
Gabriella Palmieri
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
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Jordan Jacobelli,
Jordan Jacobelli
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
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Mario Piccoli,
Mario Piccoli
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
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Luigi Frati,
Luigi Frati
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
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Angela Santoni
Angela Santoni
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
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Fabrizio Mainiero
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
Angela Gismondi
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
Alessandra Soriani
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
Marco Cippitelli
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
Gabriella Palmieri
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
Jordan Jacobelli
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
Mario Piccoli
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
Luigi Frati
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
Angela Santoni
From the *Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza,” 00161 Rome, Italy; the ‡Biotechnology Section, Istituto Nazionale per lo Studio e la Cura del Tumori, 16100 Genoa, Italy; the §Mediterranean Institute of Neurosciences “Neuromed,” 86170 Pozzilli, Italy; and the ‖Laboratory of Pathophysiology, Regina Elena Cancer Institute, 00100 Rome, Italy
Address correspondence to Fabrizio Mainiero, Department of Experimental Medicine and Pathology, University of Rome “La Sapienza,” viale Regina Elena, 324, 00161 Rome, Italy. Phone: 39-6-4468448; Fax: 39-6-4468448; E-mail: [email protected]
This work was partially supported by grants from the Italian Association for Cancer Research (AIRC), Istituto Superiore di Sanità Italy-USA “Therapy of Tumors” Program, Ministero dell'Università e della Ricerca Scientifica e Tecnologica (MURST) 40% and 60%, Ministero della Sanità, and by a Consiglio Nazionale delle Ricerche special project on Biotechnologies.
Received:
May 28 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 188 (7): 1267–1275.
Article history
Received:
May 28 1998
Citation
Fabrizio Mainiero, Angela Gismondi, Alessandra Soriani, Marco Cippitelli, Gabriella Palmieri, Jordan Jacobelli, Mario Piccoli, Luigi Frati, Angela Santoni; Integrin-mediated Ras–Extracellular Regulated Kinase (ERK) Signaling Regulates Interferon γ Production in Human Natural Killer Cells . J Exp Med 5 October 1998; 188 (7): 1267–1275. doi: https://doi.org/10.1084/jem.188.7.1267
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