Integrin-mediated ras-extracellular regulated kinase (ERK) signaling regulates interferon gamma production in human natural killer cells.
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 beta1 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 beta1 integrin-mediated Ras activation. In addition, we demonstrate that ligation of beta1 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 beta1 integrins, by delivering signals capable of triggering IFN-gamma production, may function as NK-activating receptors.
Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome "La Sapienza", 00161 Rome, Italy.
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Mainiero
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Gismondi
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A
Soriani
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M
Cippitelli
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Palmieri
J
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Jacobelli
M
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Piccoli
L
L
Frati
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Santoni
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D003432:Cross-Linking Reagents; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D003432:Cross-Linking Reagents; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D019012:Integrin beta1; D011506:Proteins; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014443:Tyrosine; D007371:Interferon-gamma; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1