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The interaction between uPAR and vitronectin triggers ligand-independent adhesion signalling by integrins

Ferraris, Gian Maria Sarra ; Schulte, Carsten ; Buttiglione, Valentina ; De Lorenzi, Valentina ; Piontini, Andrea ; Galluzzi, Massimiliano ; Podestà, Alessandro ; Madsen, Chris D LU and Sidenius, Nicolai (2014) In EMBO Journal 33(21). p.72-2458
Abstract

The urokinase-type plasminogen activator receptor (uPAR) is a non-integrin vitronectin (VN) cell adhesion receptor linked to the plasma membrane by a glycolipid anchor. Through structure-function analyses of uPAR, VN and integrins, we document that uPAR-mediated cell adhesion to VN triggers a novel type of integrin signalling that is independent of integrin-matrix engagement. The signalling is fully active on VN mutants deficient in integrin binding site and is also efficiently transduced by integrins deficient in ligand binding. Although integrin ligation is dispensable, signalling is crucially dependent upon an active conformation of the integrin and its association with intracellular adaptors such as talin. This non-canonical... (More)

The urokinase-type plasminogen activator receptor (uPAR) is a non-integrin vitronectin (VN) cell adhesion receptor linked to the plasma membrane by a glycolipid anchor. Through structure-function analyses of uPAR, VN and integrins, we document that uPAR-mediated cell adhesion to VN triggers a novel type of integrin signalling that is independent of integrin-matrix engagement. The signalling is fully active on VN mutants deficient in integrin binding site and is also efficiently transduced by integrins deficient in ligand binding. Although integrin ligation is dispensable, signalling is crucially dependent upon an active conformation of the integrin and its association with intracellular adaptors such as talin. This non-canonical integrin signalling is not restricted to uPAR as it poses no structural constraints to the receptor mediating cell attachment. In contrast to canonical integrin signalling, where integrins form direct mechanical links between the ECM and the cytoskeleton, the molecular mechanism enabling the crosstalk between non-integrin adhesion receptors and integrins is dependent upon membrane tension. This suggests that for this type of signalling, the membrane represents a critical component of the molecular clutch.

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author
; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Cell Adhesion, HEK293 Cells, Humans, Integrins, Mutation, Receptors, Urokinase Plasminogen Activator, Signal Transduction, Vitronectin, Journal Article, Research Support, Non-U.S. Gov't
in
EMBO Journal
volume
33
issue
21
pages
72 - 2458
publisher
Oxford University Press
external identifiers
  • pmid:25168639
  • scopus:84922246831
ISSN
1460-2075
DOI
10.15252/embj.201387611
language
English
LU publication?
no
id
75319cc9-efa6-49ed-9eba-27407dabeab6
date added to LUP
2016-12-06 10:15:15
date last changed
2024-06-28 20:44:16
@article{75319cc9-efa6-49ed-9eba-27407dabeab6,
  abstract     = {{<p>The urokinase-type plasminogen activator receptor (uPAR) is a non-integrin vitronectin (VN) cell adhesion receptor linked to the plasma membrane by a glycolipid anchor. Through structure-function analyses of uPAR, VN and integrins, we document that uPAR-mediated cell adhesion to VN triggers a novel type of integrin signalling that is independent of integrin-matrix engagement. The signalling is fully active on VN mutants deficient in integrin binding site and is also efficiently transduced by integrins deficient in ligand binding. Although integrin ligation is dispensable, signalling is crucially dependent upon an active conformation of the integrin and its association with intracellular adaptors such as talin. This non-canonical integrin signalling is not restricted to uPAR as it poses no structural constraints to the receptor mediating cell attachment. In contrast to canonical integrin signalling, where integrins form direct mechanical links between the ECM and the cytoskeleton, the molecular mechanism enabling the crosstalk between non-integrin adhesion receptors and integrins is dependent upon membrane tension. This suggests that for this type of signalling, the membrane represents a critical component of the molecular clutch.</p>}},
  author       = {{Ferraris, Gian Maria Sarra and Schulte, Carsten and Buttiglione, Valentina and De Lorenzi, Valentina and Piontini, Andrea and Galluzzi, Massimiliano and Podestà, Alessandro and Madsen, Chris D and Sidenius, Nicolai}},
  issn         = {{1460-2075}},
  keywords     = {{Cell Adhesion; HEK293 Cells; Humans; Integrins; Mutation; Receptors, Urokinase Plasminogen Activator; Signal Transduction; Vitronectin; Journal Article; Research Support, Non-U.S. Gov't}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{21}},
  pages        = {{72--2458}},
  publisher    = {{Oxford University Press}},
  series       = {{EMBO Journal}},
  title        = {{The interaction between uPAR and vitronectin triggers ligand-independent adhesion signalling by integrins}},
  url          = {{http://dx.doi.org/10.15252/embj.201387611}},
  doi          = {{10.15252/embj.201387611}},
  volume       = {{33}},
  year         = {{2014}},
}