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Published 31 January 2005. doi:10.1083/jcb.200404112
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 168, Number 3, 501-511
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Article

Regulation of {alpha}5ß1 integrin conformation and function by urokinase receptor binding



Ying Wei1, Ralf-Peter Czekay2, Liliane Robillard1, Matthias C. Kugler1, Feng Zhang1, Kevin K. Kim1, Jian-ping Xiong3, Martin J. Humphries4, and Harold A. Chapman1

1 Department of Medicine and Pulmonary and Critical Care Division, University of California, San Francisco, San Francisco, CA 94143
2 Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
3 Structural Biology Program, Massachusetts General Hospital, Charlestown, MA 02129
4 Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, University of Manchester, Manchester M13 9PT, England, UK

Correspondence to Harold A. Chapman: halchap{at}itsa.ucsf.edu; or Ying Wei: yingwei{at}itsa.ucsf.edu

Urokinase-type plasminogen activator receptors (uPARs), up-regulated during tumor progression, associate with ß1 integrins, localizing urokinase to sites of cell attachment. Binding of uPAR to the ß-propeller of {alpha}3ß1 empowers vitronectin adhesion by this integrin. How uPAR modifies other ß1 integrins remains unknown. Using recombinant proteins, we found uPAR directly binds {alpha}5ß1 and rather than blocking, renders fibronectin (Fn) binding by {alpha}5ß1 Arg-Gly-Asp (RGD) resistant. This resulted from RGD-independent binding of {alpha}5ß1–uPAR to Fn type III repeats 12–15 in addition to type III repeats 9–11 bound by {alpha}5ß1. Suppression of endogenous uPAR by small interfering RNA in tumor cells promoted weaker, RGD-sensitive Fn adhesion and altered overall {alpha}5ß1 conformation. A ß1 peptide (res 224NLDSPEGGF232) that models near the known {alpha}-chain uPAR-binding region, or a ß1-chain Ser227Ala point mutation, abrogated effects of uPAR on {alpha}5ß1. Direct binding and regulation of {alpha}5ß1 by uPAR implies a modified "bent" integrin conformation can function in an alternative activation state with this and possibly other cis-acting membrane ligands.

Abbreviations used in this paper: ERK, extracellular signal–regulated kinase; Fn, fibronectin; LIBS, ligand-induced binding site; Ln-5, laminin-5; PAI-1, plasminogen activator inhibitor-1; RGD, Arg-Gly-Asp; siRNA, small interfering RNA; suPAR, soluble uPAR; Tet, tetracycline; uPA, urokinase-type plasminogen activator; uPAR, uPA receptor; Vn, vitronectin.


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