Affinity modulation of very late antigen-5 through phosphatidylinositol 3-kinase in mast cells

J Immunol. 1999 Mar 1;162(5):2850-7.

Abstract

Adhesiveness of integrins is up-regulated rapidly by a number of molecules, including growth factors, cytokines, chemokines, and other cell surface receptors, through a mechanism termed inside-out signaling. The inside-out signaling pathways are thought to alter integrin affinity for ligand, or cell surface distribution of integrin by diffusion/clustering. However, it remains to be clarified whether any physiologically relevant agonists induce a rapid change in the affinity of beta1 integrins and how ligand-binding affinity is modulated upon stimulation. In this study, we reported that affinity of beta1 integrin very late Ag-5 (VLA-5) for fibronectin was rapidly increased in bone marrow-derived mast cells by Ag cross-linking of FcepsilonRI. Ligand-binding affinity of VLA-5 was also augmented by receptor tyrosine kinases when the phospholipase Cgamma-1/protein kinase C pathway was inhibited. Wortmannin suppressed induction of the high affinity state VLA-5 in either case. Conversely, introduction of a constitutively active p110 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) increased the binding affinity for fibronectin. Failure of a constitutively active Akt to stimulate adhesion suggested that the affinity modulation mechanisms mediated by PI 3-kinase are distinct from the mechanisms to control growth and apoptosis by PI 3-kinase. Taken together, our findings demonstrated that the increase of affinity of VLA-5 was induced by physiologically relevant stimuli and PI 3-kinase was a critical affinity modulator of VLA-5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Cell Line
  • Fibronectins / physiology
  • Humans
  • Mast Cells / metabolism*
  • Mice
  • Phosphatidylinositol 3-Kinases / physiology*
  • Platelet-Derived Growth Factor / pharmacology
  • Receptors, Fibronectin / metabolism*
  • Receptors, IgE / physiology
  • Tetradecanoylphorbol Acetate / pharmacology
  • Type C Phospholipases / physiology
  • Wortmannin

Substances

  • Androstadienes
  • Fibronectins
  • Platelet-Derived Growth Factor
  • Receptors, Fibronectin
  • Receptors, IgE
  • Phosphatidylinositol 3-Kinases
  • Type C Phospholipases
  • Tetradecanoylphorbol Acetate
  • Wortmannin