Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.21.73 (
urokinase-type plasminogen activator
)
10,685
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Pharmacological interventions to enhance fibrinolysis are effective for treating thrombotic disorders. Utilizing the in vitro U937 cell line-based fibrin degradation assay, we had previously found a cyclic pentapeptide malformin A
1
(MA
1
) as a novel activating compound for cellular fibrinolytic activity. The mechanism by which MA
1
enhances cellular fibrinolytic activity remains unknown. In the present study, we show that
RSK1
is a crucial mediator of MA
1
-induced cellular fibrinolysis. Treatment with rhodamine-conjugated MA
1
showed that MA
1
localizes mainly in the cytoplasm of U937 cells. Screening with an antibody macroarray revealed that MA
1
induces the phosphorylation of
RSK1
at Ser380 in U937 cells. SL0101, an inhibitor of RSK, inhibited MA
1
-induced fibrinolytic activity, and CRISPR/Cas9-mediated knockout of
RSK1
but not RSK2 suppressed MA
1
-enhanced fibrinolysis in U937 cells. Synthetic active MA
1
derivatives also induced the phosphorylation of
RSK1
. Furthermore, MA
1
treatment stimulated phosphorylation of ERK1/2 and MEK1/2. PD98059, an inhibitor of MEK1/2, inhibited MA
1
-induced phosphorylation of
RSK1
and ERK1/2, indicating that MA
1
induces the activation of the MEK-ERK-RSK pathway. Moreover, MA
1
upregulated the expression of
urokinase-type plasminogen activator
(
uPA
) and increased
uPA
secretion. These inductions were abrogated in
RSK1
knockout cells. These results indicate that
RSK1
is a key regulator of MA
1
-induced extracellular fibrinolytic activity.
...
PMID:Involvement of RSK1 activation in malformin-enhanced cellular fibrinolytic activity. 2961 89
