JCB logo
amgmicro.com
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 650K)
Right arrow PPT slides of all figures
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JCB
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hato, T.
Right arrow Articles by Shattil, S. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hato, T.
Right arrow Articles by Shattil, S. J.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

© The Rockefeller University Press, 0021-9525/1998//1685 $5.00
The Journal of Cell Biology, Volume 141, Number 7, , 1998 1685-1695

Articles

Complementary Roles for Receptor Clustering and Conformational Change in the Adhesive and Signaling Functions of Integrin {alpha}IIbβ3



Takaaki Hato*,§, Nisar Pampori*, and Sanford J. Shattil*,{ddagger}

* Department of Vascular Biology, {ddagger} Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California; and § Ehime University School of Medicine, Ehime, Japan

Integrin {alpha}IIbβ3 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 {alpha}IIbβ3 function, {alpha}IIb was fused at its cytoplasmic tail to one or two FKBP12 repeats (FKBP). These modified {alpha}IIb subunits were expressed with β3 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 {alpha}IIbβ3 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 {alpha}IIbβ3 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 {alpha}IIbβ3 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 {alpha}IIbβ3 in platelets.

Abbreviations used in this paper: ECL, enhanced chemiluminescence; FKBP, FK506 binding protein, or FKBP12; vWf, von Willebrand factor.

These studies were supported, in part by grants from the National Institutes of Health (HL56595, HL57900).

Address all correspondence to Dr. Shattil, Department of Vascular Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., VB-5, La Jolla, CA 92037. Tel.: (619) 784-7148. Fax: (619) 784-7422. E-mail: shattil{at}scripps.edu


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents