The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/10/1267/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 7, October 5, 1998 1267-1275

Articles

Integrin-mediated Ras–Extracellular Regulated Kinase (ERK) Signaling Regulates Interferon {gamma} Production in Human Natural Killer Cells

Fabrizio Mainiero*, Angela Gismondi*, Alessandra Soriani*, Marco Cippitelli*,||, Gabriella Palmieri*,{ddagger}, Jordan Jacobelli*, Mario Piccoli*, Luigi Frati*,§, and Angela Santoni*,||

From the * Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome "La Sapienza," 00161 Rome, Italy; the {ddagger} 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

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 {gamma} (IFN-{gamma}) 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-{gamma} production, may function as NK-activating receptors.

Key Words: natural killer cells • integrins • Ras/mitogen-activated protein kinase pathway • interferon {gamma}

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: asantoni{at}axcasp.caspur.it

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.

Abbreviations used: Erk, extracellular signal–regulated kinase; FN, fibronectin; Fak, focal adhesion kinase; GAM, goat anti–mouse IgG F(ab')2; Grb2, growth factor–bound protein 2; GST, glutathione S-transferase; Jnk, c-Jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; MBP, myelin basic protein; MEK, MAPK kinase; Pyk-2, proline-rich tyrosine kinase 2.


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