BINDING OF UROKINASE-TYPE PLASMINOGEN-ACTIVATOR TO ITS RECEPTOR IN MCF-7 CELLS ACTIVATES EXTRACELLULAR SIGNAL-REGULATED KINASE-1 AND KINASE-2 WHICH IS REQUIRED FOR INCREASED CELLULAR MOTILITY
Dhd. Nguyen et al., BINDING OF UROKINASE-TYPE PLASMINOGEN-ACTIVATOR TO ITS RECEPTOR IN MCF-7 CELLS ACTIVATES EXTRACELLULAR SIGNAL-REGULATED KINASE-1 AND KINASE-2 WHICH IS REQUIRED FOR INCREASED CELLULAR MOTILITY, The Journal of biological chemistry, 273(14), 1998, pp. 8502-8507
Binding of urokinase-type plasminogen activator (uPA) to its receptor,
uPAR, regulates cellular adhesion, migration, and tumor cell invasion
, Some of these activities may reflect the ability of uPAR to initiate
signal transduction even though this receptor is linked to the plasma
membrane only by a glycosylphosphatidylinositol anchor, In this study
, we demonstrated that single-chain uPA activates extracellular signal
-regulated kinase 1 (ERK1) and ERK2 in MCF-7 breast cancer cells. Phos
phorylation of ERK1 and ERK2 was increased 1 min after adding uPA and
returned to baseline levels by 5 min, The amino-terminal fragment (ATF
) of uPA, which binds to uPAR but lacks proteinase activity, also acti
vated ERK1 and ERK2. Responses to uPA and ATF were eliminated when the
cells were pretreated with PD098059, an inhibitor of mitogen-activate
d protein kinase kinase, uPA and ATF promoted the migration of MCF-9 c
ells across serum-coated Transwell membranes in vitro, Migration was i
ncreased 2.1 +/- 0.4-fold when uPA was added to the top chamber, 4.8 /- 0.8-fold when uPA was added to the bottom chamber, and 7.7 +/- 1.0-
fold when uPA was added to both chambers, MCF-7 cells that were pulse-
exposed to uPA for 30 min, and then washed to remove unbound ligand, d
emonstrated increased motility even though migration was allowed to oc
cur for 24 h, PD098059 completely neutralized the effects of uPA on MC
F-7 cellular-motility, irrespective of whether the uPA was present for
the entire. motility assay or administered by pulse-exposure, These r
esults demonstrate a novel, receptor-dependent signaling activity whic
h is required for uPA-stimulated breast cancer cell migration.