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A more recent version of this article appeared on August 1, 2002
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Submitted on November 1, 2001
Revised on May 10, 2002
Accepted on May 17, 2002
1 Lung Inflammation Group, Centre for Inflammation Research, Hugh Robson Building, Medical School, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK
2 Departments of Medicine and Biomolecular Chemistry, University of Wisconsin-Madison, 1300 University Avenue, Madison, WI 53706
* Corresponding author. E-mail address: t.sethi{at}ed.ac.uk.
CD98, an early marker of T-cell activation, is an important regulator of integrin-mediated adhesion events. Previous studies suggest that CD98 is coupled to both cellular activation and transformation and is involved in the pathogenesis of viral infection, inflammatory disease and cancer. Understanding of the molecular mechanisms underlying CD98 activity may have far-reaching practical applications in the development of novel therapeutic strategies in these disease states. Using small cell lung cancer cell lines, which are non-adherent, non-polarized and highly express CD98, we show that, in vitro, under physiological conditions, CD98 is constitutively associated with ß1 integrins regardless of activation status. Cross-linking CD98 with the monoclonal antibody 4F2 stimulated, PI 3-kinase, PI(3,4,5)P3 and protein kinase B in the absence of integrin ligation or ECM engagement. Furthermore, cross-linking CD98 promoted anchorage-independent growth. Using fibroblasts derived from ß1 integrin null stem cells (GD25), wild type GD25ß1 or GD25 cells expressing a mutation preventing ß1 integrin-dependent FAK phosphorylation we demonstrate that a functional ß1 integrin is required for CD98 signaling. We propose that by cross-linking CD98, it acts as a "molecular facilitator" in the plasma membrane, clustering ß1 integrins to form high-density complexes. This results in integrin activation, integrin-like signaling and anchorage-independent growth. Activation of PI 3-kinase may, in part, explain cellular transformation seen on overexpressing CD98. These results may provide a paradigm for events involved in such diverse processes as inflammation and viral-induced cell fusion.
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