Regulation of human squamous cell carcinoma plasma membrane associated urokinase plasminogen activator by epidermal growth factor.
The amino terminal portion of urokinase type plasminogen activator (uPA) interacts with a cell surface binding protein/receptor that recognizes a region of the molecule autonomous from that of the catalytic domain of the enzyme, which mediates the conversion of plasminogen to plasmin. The expression of cell surface uPA receptors (uPA-Rs) and their association with uPA have been implicated in cellular invasion and tissue destruction. Treatment of A431 squamous carcinoma cells (SqCC) with epidermal growth factor (EGF) has previously been shown to result in an induction of the synthesis and extracellular accumulation of uPA and the plasminogen-dependent proteolysis of extracellular matrix (ECM). Regulation of cell membrane associated uPA activity by EGF and its influence on uPA-R expression in A431 cells, which possess an unusually large number of EGF-R (greater than 10(6)), and in an EGF-R expression variant (A431/A5), which contains 20-fold fewer cell surface EGF-R, were assessed. Exposure to 5-50 ng/mL of EGF for 24 hr enhanced uPA activity 2- to 3-fold in partially purified membrane preparations derived from A431 cells in a concentration dependent manner. In contrast, no changes in tissue type plasminogen activator (tPA) activity were detected under similar conditions. A431/A5 cell membrane preparations did not exhibit such an EGF mediated response. In accord with EGF enhanced uPA activity, a 2-fold increase in immunoreactive cell surface associated uPA was observed in A431 cells using indirect immunofluorescence staining. The increase in cell surface uPA produced by exposure to EGF required protein synthesis and could be blocked by cycloheximide.(ABSTRACT TRUNCATED AT 250 WORDS)
Niedbala
M J
MJ
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510.
Bajetta
S
S
Carbone
R
R
Sartorelli
A C
AC
D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000648:ultrastructure; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000378:metabolism*; D006801:Humans; D010960:Plasminogen Activators / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D005343:Fibrinolytic Agents; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D004815:Epidermal Growth Factor; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator