J. Exp. Med., Volume 188, Number 7, October 5, 1998 1267-1275

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

By Fabrizio Mainiero,^* Angela Gismondi,^* Alessandra Soriani,^* Marco Cippitelli,^* Gabriella Palmieri,^* 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  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 1 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 1 integrin-mediated Ras activation. In addition, we demonstrate that ligation of 1 integrins results in the stimulation of interferon  (IFN-) production, which is under the control of extracellular signal-regulated kinase 2 activation. Overall, our data indicate that 1 integrins, by delivering signals capable of triggering IFN- production, may function as NK-activating receptors.

natural killer cells;  integrins;  Ras/mitogen-activated protein kinase pathway;  interferon

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