Degradation of internalized αvβ5 integrin is controlled by uPAR bound uPA: effect on β1 integrin activity and α-SMA stress fiber assembly

PLoS One. 2012;7(3):e33915. doi: 10.1371/journal.pone.0033915. Epub 2012 Mar 21.


Myofibroblasts (Mfs) that persist in a healing wound promote extracellular matrix (ECM) accumulation and excessive tissue contraction. Increased levels of integrin αvβ5 promote the Mf phenotype and other fibrotic markers. Previously we reported that maintaining uPA (urokinase plasminogen activator) bound to its cell-surface receptor, uPAR prevented TGFβ-induced Mf differentiation. We now demonstrate that uPA/uPAR controls integrin β5 protein levels and in turn, the Mf phenotype. When cell-surface uPA was increased, integrin β5 levels were reduced (61%). In contrast, when uPA/uPAR was silenced, integrin β5 total and cell-surface levels were increased (2-4 fold). Integrin β5 accumulation resulted from a significant decrease in β5 ubiquitination leading to a decrease in the degradation rate of internalized β5. uPA-silencing also induced α-SMA stress fiber organization in cells that were seeded on collagen, increased cell area (1.7 fold), and increased integrin β1 binding to the collagen matrix, with reduced activation of β1. Elevated cell-surface integrin β5 was necessary for these changes after uPA-silencing since blocking αvβ5 function reversed these effects. Our data support a novel mechanism by which downregulation of uPA/uPAR results in increased integrin αvβ5 cell-surface protein levels that regulate the activity of β1 integrins, promoting characteristics of the persistent Mf.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actins / metabolism
  • Antibodies / immunology
  • Cells, Cultured
  • Collagen / metabolism
  • Humans
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism
  • Myofibroblasts / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptors, Urokinase Plasminogen Activator / antagonists & inhibitors
  • Receptors, Urokinase Plasminogen Activator / genetics
  • Receptors, Urokinase Plasminogen Activator / metabolism*
  • Receptors, Vitronectin / immunology
  • Receptors, Vitronectin / metabolism*
  • Transforming Growth Factor beta / metabolism
  • Ubiquitination
  • Urokinase-Type Plasminogen Activator / antagonists & inhibitors
  • Urokinase-Type Plasminogen Activator / genetics
  • Urokinase-Type Plasminogen Activator / metabolism*


  • ACTA2 protein, human
  • Actins
  • Antibodies
  • Integrin beta1
  • RNA, Small Interfering
  • Receptors, Urokinase Plasminogen Activator
  • Receptors, Vitronectin
  • Transforming Growth Factor beta
  • integrin alphaVbeta5
  • Collagen
  • Urokinase-Type Plasminogen Activator