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J. Cell Biol.,
Volume 141, Number 7, June 29, 1998 1685-1695
IIb
3
* Department of Vascular Biology, Integrin Department of Molecular and Experimental Medicine, The Scripps Research Institute, La
Jolla, California; and § Ehime University School of Medicine, Ehime, Japan
IIb
3 mediates platelet aggregation
and "outside-in" signaling. It is regulated by changes in
receptor conformation and affinity and/or by lateral
diffusion and receptor clustering. To document the relative contributions of conformation and clustering to
IIb3 function, IIb was fused at its cytoplasmic tail to one or two FKBP12 repeats (FKBP). These modified
IIb subunits were expressed with 3 in CHO cells, and
the heterodimers could be clustered into morphologically detectable oligomers upon addition of AP1510, a
membrane-permeable, bivalent FKBP ligand. Integrin clustering by AP1510 caused binding of fibrinogen and
a multivalent (but not monovalent) fibrinogen-mimetic
antibody. However, ligand binding due to clustering
was only 25-50% of that observed when IIb3 affinity
was increased by an activating antibody or an activating
mutation. The effects of integrin clustering and affinity modulation were additive, and clustering promoted irreversible ligand binding. Clustering of IIb3 also promoted cell adhesion to fibrinogen or von Willebrand
factor, but not as effectively as affinity modulation.
However, clustering was sufficient to trigger fibrinogen-independent tyrosine phosphorylation of pp72Syk
and fibrinogen-dependent phosphorylation of
pp125FAK, even in non-adherent cells. Thus, receptor
clustering and affinity modulation play complementary
roles in IIb3 function. Affinity modulation is the predominant regulator of ligand binding and cell adhesion,
but clustering increases these responses further and
triggers protein tyrosine phosphorylation, even in the
absence of affinity modulation. Both affinity modulation and clustering may be needed for optimal function
of IIb3 in platelets.
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