Regulated localization confers multiple functions on the protease urokinase plasminogen activator.
We have investigated the role of the plasminogen activation cascade in skeletal muscle differentiation. Migrating, undifferentiated myoblasts express urokinase plasminogen activator (uPA) and its cell surface receptor (uPAR). Consequently, uPA is localized predominantly to the cell surface. Preventing uPA from associating with its receptor with a noncatalytic form of uPA (NC-uPA) hinders migration of myoblasts and inhibits differentiation. When myoblasts reach confluence, cease migrating, and start to differentiate, uPAR gets downregulated, and uPA becomes redistributed from the cell surface to the extracellular space. The function of uPA at this stage was tested using the protease inhibitors aprotinin, alpha2-antiplasmin, or plasminogen activator inhibitor-1 (PAI-1). Contrary to the role of cell-associated uPA, inhibition of soluble uPA/plasmin stimulates differentiation of myoblasts. Aprotinin can inhibit activation of latent TGFbeta and stimulates differentiation, suggesting PAI-1 and alpha2-antiplasmin also may stimulate differentiation via this mechanism. These data suggest that regulation of uPA localization allows a dual function for this protease in regulating cell migration and controlling cell differentiation.
Wells
J M
JM
Department of Pharmacology, University Medical Center at Stony Brook, New York 11794-8651, USA.
Strickland
S
S
D000818:Animals; D015152:Blotting, Northern; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D002465:Cell Movement / Q000502:physiology*; D005341:Fibrinolysin / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000166:cytology* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000737:chemistry / Q000166:cytology* / Q000201:enzymology; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology; D010960:Plasminogen Activators / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D012995:Solubility; D014568:Urokinase-Type Plasminogen Activator / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D017395:Plasminogen Activator Inhibitor 1; C524899:Plaur protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D010960:Plasminogen Activators; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator