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Department of Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
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 ß1 integrins and how ligand-binding affinity
is modulated upon stimulation. In this study, we reported that affinity
of ß1 integrin very late Ag-5 (VLA-5) for fibronectin was
rapidly increased in bone marrow-derived mast cells by Ag cross-linking
of Fc
RI. Ligand-binding affinity of VLA-5 was also augmented by
receptor tyrosine kinases when the phospholipase C
-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.
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