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uPAR-induced cell adhesion and migration : vitronectin provides the key

Madsen, Chris D LU ; Ferraris, Gian Maria Sarra; Andolfo, Annapaola; Cunningham, Orla and Sidenius, Nicolai (2007) In Journal of Cell Biology 177(5). p.39-927
Abstract

Expression of the membrane receptor uPAR induces profound changes in cell morphology and migration, and its expression correlates with the malignant phenotype of cancers. To identify the molecular interactions essential for uPAR function in these processes, we carried out a complete functional alanine scan of uPAR in HEK293 cells. Of the 255 mutant receptors characterized, 34 failed to induce changes in cell morphology. Remarkably, the molecular defect of all of these mutants was a specific reduction in integrin-independent cell binding to vitronectin. A membrane-tethered plasminogen activator inhibitor-1, which has the same binding site in vitronectin as uPAR, replicated uPAR-induced changes. A direct uPAR-vitronectin interaction is... (More)

Expression of the membrane receptor uPAR induces profound changes in cell morphology and migration, and its expression correlates with the malignant phenotype of cancers. To identify the molecular interactions essential for uPAR function in these processes, we carried out a complete functional alanine scan of uPAR in HEK293 cells. Of the 255 mutant receptors characterized, 34 failed to induce changes in cell morphology. Remarkably, the molecular defect of all of these mutants was a specific reduction in integrin-independent cell binding to vitronectin. A membrane-tethered plasminogen activator inhibitor-1, which has the same binding site in vitronectin as uPAR, replicated uPAR-induced changes. A direct uPAR-vitronectin interaction is thus both required and sufficient to initiate downstream changes in cell morphology, migration, and signal transduction. Collectively these data demonstrate a novel mechanism by which a cell adhesion molecule lacking inherent signaling capability evokes complex cellular responses by modulating the contact between the cell and the matrix without the requirement for direct lateral protein-protein interactions.

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author
publishing date
type
Contribution to journal
publication status
published
keywords
Amino Acid Motifs, Animals, Binding Sites, CHO Cells, Cell Adhesion, Cell Line, Cell Movement, Cricetinae, Cricetulus, Genetic Complementation Test, Humans, Mutagenesis, Site-Directed, Protein Interaction Mapping, Receptors, Cell Surface, Receptors, Urokinase Plasminogen Activator, Signal Transduction, Vitronectin, Journal Article, Research Support, Non-U.S. Gov't
in
Journal of Cell Biology
volume
177
issue
5
pages
39 - 927
publisher
Rockefeller University Press
external identifiers
  • scopus:34249870363
ISSN
0021-9525
DOI
10.1083/jcb.200612058
language
English
LU publication?
no
id
4e062c9b-e6a1-46be-bf77-b9bf035a9680
date added to LUP
2016-12-06 10:19:03
date last changed
2017-11-05 05:10:37
@article{4e062c9b-e6a1-46be-bf77-b9bf035a9680,
  abstract     = {<p>Expression of the membrane receptor uPAR induces profound changes in cell morphology and migration, and its expression correlates with the malignant phenotype of cancers. To identify the molecular interactions essential for uPAR function in these processes, we carried out a complete functional alanine scan of uPAR in HEK293 cells. Of the 255 mutant receptors characterized, 34 failed to induce changes in cell morphology. Remarkably, the molecular defect of all of these mutants was a specific reduction in integrin-independent cell binding to vitronectin. A membrane-tethered plasminogen activator inhibitor-1, which has the same binding site in vitronectin as uPAR, replicated uPAR-induced changes. A direct uPAR-vitronectin interaction is thus both required and sufficient to initiate downstream changes in cell morphology, migration, and signal transduction. Collectively these data demonstrate a novel mechanism by which a cell adhesion molecule lacking inherent signaling capability evokes complex cellular responses by modulating the contact between the cell and the matrix without the requirement for direct lateral protein-protein interactions.</p>},
  author       = {Madsen, Chris D and Ferraris, Gian Maria Sarra and Andolfo, Annapaola and Cunningham, Orla and Sidenius, Nicolai},
  issn         = {0021-9525},
  keyword      = {Amino Acid Motifs,Animals,Binding Sites,CHO Cells,Cell Adhesion,Cell Line,Cell Movement,Cricetinae,Cricetulus,Genetic Complementation Test,Humans,Mutagenesis, Site-Directed,Protein Interaction Mapping,Receptors, Cell Surface,Receptors, Urokinase Plasminogen Activator,Signal Transduction,Vitronectin,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {06},
  number       = {5},
  pages        = {39--927},
  publisher    = {Rockefeller University Press},
  series       = {Journal of Cell Biology},
  title        = {uPAR-induced cell adhesion and migration : vitronectin provides the key},
  url          = {http://dx.doi.org/10.1083/jcb.200612058},
  volume       = {177},
  year         = {2007},
}