Cross-linking CD98 promotes integrin-like signaling and anchorage-independent growth

Robert C Rintoul, Robert C Buttery, Alison C MacKinnon, Weng S. Wong, Deane Mosher, Christopher Haslett, Tariq Sethi

Research output: Contribution to journalArticlepeer-review

Abstract

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 nonadherent, nonpolarized, and highly express CD98, we show that, in vitro, under physiological conditions, CD98 is constitutively associated with beta1 integrins regardless of activation status. Cross-linking CD98 with the monoclonal antibody 4F2 stimulated phosphatidylinositol (PI) 3-kinase, PI(3,4,5)P(3), and protein kinase B in the absence of integrin ligation or extracellular matrix engagement. Furthermore, cross-linking CD98 promoted anchorage-independent growth. Using fibroblasts derived from beta1 integrin null stem cells (GD25), wild-type GD25beta1, or GD25 cells expressing a mutation preventing beta1 integrin-dependent FAK phosphorylation, we demonstrate that a functional beta1 integrin is required for CD98 signaling. We propose that by cross-linking CD98, it acts as a "molecular facilitator" in the plasma membrane, clustering beta1 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.
Original languageEnglish
Pages (from-to)2841-52
JournalMolecular Biology of the Cell
Volume13
Issue number82002
DOIs
Publication statusPublished - Aug 2002

Keywords

  • Amino Acids/metabolism
  • Antibodies, Monoclonal
  • Antigens, CD29
  • Antigens, CD98
  • Cell Adhesion
  • Cell Division
  • Cross-Linking Reagents
  • Enzyme Activation
  • Enzyme Inhibitors/metabolism
  • Fibroblasts
  • Flow Cytometry
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • Humans
  • Immunohistochemistry
  • Neuropeptides
  • Phosphatidylinositol 3-Kinases
  • Phosphatidylinositol Phosphates
  • Protein-Tyrosine Kinases
  • Signal Transduction
  • Tumor Cells, Cultured

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