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Vol. 16, Issue 6, 2972-2983, June 2005
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1 Integrins and Modulate Adhesion-dependent Signaling
* Department of Experimental Pathology and Oncology, University of Firenze, 50134 Firenze, Italy;
Department of Clinical Physiopathology, University of Firenze, 50139 Firenze, Italy;
Department of Genetics, Biochemistry, and Biology, University of Torino, 10133 Torino, Italy;
|| Department of Biotechnology and Biosciences, University of Milano Bicocca, 20126 Milano, Italy; and
¶ Center for Health Sciences and College of Osteopathic Medicine, Oklahoma State University, Tulsa, OK 74107
Submitted October 28, 2004;
Revised March 14, 2005;
Accepted March 17, 2005
Monitoring Editor: Martin A. Schwartz
Adhesive receptors of the integrin family are primarily involved in cell–extracellular matrix adhesion. Additionally, integrins trigger multiple signaling pathways that are involved in cell migration, proliferation, survival, and differentiation. We previously demonstrated that the activation of integrins containing the 
1 subunit leads to a selective increase in potassium currents carried by the human ether-a-go-go-related gene (hERG) channels in neuroblastoma and leukemia cells; this current activation modulates adhesion-dependent differentiation in these cells. We hypothesized that the cross-talk between integrins and hERG channels could be traced back to the assembly of a macromolecular signaling complex comprising the two proteins. We tested this hypothesis in both SH-SY5Y neuroblastoma cells and in human embryonic kidney 293 cells stably transfected with hERG1 and, therefore, expressing only the full-length hERG1 protein on the plasma membrane. The 1 integrin and hERG1 coprecipitate in these cells and colocalize in both intracellular and surface membrane compartments. The two proteins also coprecipitate with caveolin-1, suggesting the localization of the complex in lipid rafts/caveolae. hERG1-transfected cells undergo an activation of hERG currents after 1 integrin-mediated adhesion to fibronectin; concomitant with this activation, the focal adhesion kinase associates with the hERG1 protein and becomes tyrosine phosphorylated. Using hERG1-specific inhibitors, we show that the tyrosine phosphorylation of focal adhesion kinase is strictly dependent on hERG channel activity. Similarly, the activity of the small GTPase Rac1 turned out to be dependent on hERG currents. On the whole, these data indicate that the hERG1 protein associates with 1 integrins and modulates adhesion receptor signaling.
Abbreviations used: ECM, extracellular matrix; FAK, focal adhesion kinase; FN, fibronectin; GIRK, G protein-gated inwardly rectifying K+; hERG1, human ether-a-go-go-related gene 1; IF, immunofluorescence; IP, immunoprecipitation(ed); p-Tyr, phosphotyrosine; WB, Western blot.
These authors contributed equally to this article.
Address correspondence to: Annarosa Arcangeli (annarosa.arcangeli{at}unifi.it).
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