Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
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Target Concepts:
Gene/Protein
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Query: EC:3.4.21.73 (
urokinase-type plasminogen activator
)
10,685
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Urokinase-type plasminogen activator (
uPA
) is a serine proteinase that, upon binding to its receptor (uPAR), catalyzes the conversion of plasminogen into plasmin on the cell surface. Our previous studies indicate that
uPA
and uPAR expression increase in the ischemic brain during the recovery phase from an acute ischemic injury and that
uPA
binding to uPAR promotes neurological recovery after an acute ischemic stroke. Here, we used male mice genetically deficient on either
uPA
(
uPA
-/-
) or uPAR (uPAR
-/-
) or with a four-amino acid substitution into the growth factor domain of
uPA
that abrogates its binding to uPAR (
Plat
GFDhu/GFDhu
) to investigate the mechanism whereby
uPA
promotes neurorepair in the ischemic brain. We found that neurons release
uPA
and astrocytes recruit uPAR to their plasma membrane during the recovery phase from a hypoxic injury and that binding of neuronal
uPA
to astrocytic uPAR induces astrocytic activation by a mechanism that does not require plasmin generation, but instead is mediated by
extracellular signal-regulated kinase 1
/2 (ERK1/2)-regulated phosphorylation of the signal transducer and activator of transcription 3 (STAT3). We report that
uPA
/uPAR binding is necessary and sufficient to induce astrocytic activation in the ischemic brain and that astrocytes activated by neuronal
uPA
promote synaptic recovery in neurons that have suffered an acute hypoxic injury via a mechanism mediated by astrocytic thrombospondin-1 (TSP1) and synaptic low-density lipoprotein receptor-related protein-1 (LRP1). In summary, we show that
uPA
/uPAR-induced astrocytic activation mediates a cross talk between astrocytes and injured neurons that promotes synaptic recovery in the ischemic brain.
SIGNIFICANCE STATEMENT
To date, there is no therapeutic strategy to promote synaptic recovery in the injured brain. Here, we show that neurons release
urokinase-type plasminogen activator
(
uPA
) and astrocytes recruit the
uPA
receptor (uPAR) to their plasma membrane during the recovery phase from a hypoxic injury. We found that binding of neuronal
uPA
to astrocytic uPAR promotes astrocytic activation and that astrocytes activated by
uPA
-uPAR binding promote synaptic recovery in neurons that have suffered a hypoxic injury by a mechanism that does not require plasmin generation, but instead is mediated by ERK1/2-regulated STAT3 phosphorylation, astrocytic thrombospondin-1 (TSP1) and synaptic low-density lipoprotein receptor-related protein-1 (LRP1). Our work unveils a new biological function for
uPA
-uPAR as mediator of a neuron-astrocyte cross talk that promotes synaptic recovery in the ischemic brain.
...
PMID:A Cross Talk between Neuronal Urokinase-type Plasminogen Activator (uPA) and Astrocytic uPA Receptor (uPAR) Promotes Astrocytic Activation and Synaptic Recovery in the Ischemic Brain. 2893 68
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