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
Date
04/04/2012Pubmed ID
22470492Pubmed Central ID
PMC3309951DOI
10.1371/journal.pone.0033915Scopus ID
2-s2.0-84863358460 (requires institutional sign-in at Scopus site) 21 CitationsAbstract
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.
Author List
Wang L, Pedroja BS, Meyers EE, Garcia AL, Twining SS, Bernstein AMAuthor
Sally S. Twining PhD Assistant Dean, Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ActinsAntibodies
Cells, Cultured
Collagen
Humans
Integrin beta1
Myofibroblasts
RNA Interference
RNA, Small Interfering
Receptors, Urokinase Plasminogen Activator
Receptors, Vitronectin
Transforming Growth Factor beta
Ubiquitination
Urokinase-Type Plasminogen Activator
