Role of urokinase receptor and caveolin in regulation of integrin signaling.
Emerging evidence indicates a prominent role for non-integrin membrane adaptors in the dynamic regulation of integrin signaling. Two such integrin-associated proteins are the glycosylphosphatidyl-inositol (GPI)-linked urokinase receptor (u-PAR) and the cholesterol-binding protein, caveolin-1. Recent studies indicate that caveolin is required for the association of Src-family kinases with beta 1 integrins. Loss of caveolin/beta 1 integrin association results in loss of ligand-induced focal adhesion kinase (FAK) phosphorylation and impaired development of focal adhesion sites. Similarly, fibronectin-dependent fyn signaling through alpha 5/beta 1 leading to mitogen-activated protein (MAP) kinase activation requires the presence of caveolin-1. Caveolin binds Src-family kinases and such binding maintains these kinases in an inactive state. Current evidence favors a model in which ligand-induced integrin clustering, a central event in integrin activation, promotes caveolin oligomerization leading to release and/or activation of Src-family kinases and initiation of integrin signaling. The presence of u-PAR promotes these events because the extracellular domain(s) of u-PAR binds to beta 1 and beta 2 integrins and the GPI anchor of u-PAR, like that of other GPI-anchored proteins, interacts with cholesterol-rich membrane domains enriched in caveolin and tyrosine kinases. Integrins, caveolin, and u-PAR form interdependent functional complexes, promoting the association of integrins with caveolin-rich signaling domains. During states of accelerated cellular migration, such as during inflammation and tumorigenesis, expression of u-PAR may be a key facilitator of integrin signaling. Interruption of u-PAR/integrin interactions may be a strategy to regulate cellular migration in these settings.
Chapman
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Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. hchapman@rics.bwh.harvard.edu
Wei
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Simon
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Waltz
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DA
D000818:Animals; D051242:Caveolin 1; D022461:Caveolins; D002448:Cell Adhesion; D002465:Cell Movement; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D015398:Signal Transduction
C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D019012:Integrin beta1; D016023:Integrins; D008024:Ligands; D008565:Membrane Proteins; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator