The binding of Plasminogen activator, urokinase (PLAU
(UPA)) to its glycosyl-phosphatidyl-inositol (GPI) anchored Plasminogen
activator, urokinase receptor (PLAUR (UPAR) (uPAR)) mediates
a variety of functions including vascular homeostasis, inflammation and tissue repair
PLAU (UPA) plays a pivotal role in the regulation of cell
adhesion and migration during tissue remodeling and activates intracellular signaling
upon binding to certain receptors on the cell surface.
The PLAU (UPA) is an important component of the
extracellular protease system because it specifically converts
Plasminogen into Plasmin .
The tissue-type PLAU (UPA) is mainly involved in
fibrinolysis, PLAU (UPA) can directly activate and be
released from extracellular matrix by a number of growth factors, e.g. Hepatocyte growth
factor (HGF) , . Growth
factors bind to their receptors on the cell surface and activate intracellular signaling
pathways that regulate the cell behavior. HGF activates
Phosphatidylinositol-3-kinase (PI3K) and V-akt murine
thymoma viral oncogene homolog 1 (AKT(PKB)) signaling
pathways via adaptor protein GRB2-associated binding protein 1
PLAUR (UPAR) is also a high-affinity receptor for the
extracellular matrix protein Vitronectin.
Vitronectin binds to alpha-8/beta-1
integrin and PLAUR (UPAR) to facilitate
adhesion of cells. Further, binding of PLAU (UPA) to
PLAUR (UPAR) strongly promotes
Vitronectin binding to PLAUR
(UPAR) . In addition,
Vitronectin binds to Serpin peptidase inhibitor, clade E
(nexin, plasminogen activator inhibitor type 1), member 1
(PAI1) and stabilizes its inhibitory activity.
PAI1 and PLAUR (UPAR) compete
for binding to Vitronectin.
PLAUR (UPAR) is functionally associated with the Casein
kinase 2, beta polypeptide (Casein kinase II, beta chain
(Phosvitin)) that form an active complex with Casein kinase 2, alpha
(Casein kinase II, alpha chains). Cell surface-located
Casein kinase II can phosphorylate
Vitronectin. Vitronectin is
selectively phosphorylated by Casein kinase II in a
PLAU (UPA)/PLAUR (UPAR)-dependent manner and phosphorylated
Vitronectin is a better ligand for integrins and
PLAUR (UPAR) . PLAUR
(UPAR) and Casein kinase II form a functional
complex with the shuttle protein Nucleolin.
Nucleolin is an abundant nuclear phosphoprotein that
shuttles between the nucleus and cytoplasm and can translocate to the cell surface.
PLAU (UPA) can induce cell proliferation through the
activation of the complex that includes PLAUR (UPAR),
Casein kinase II and Nucleolin
PLAU (UPA) activates a number of signaling pathways that
regulate cytoskeleton remodeling. On the cell surface, PLAU
(UPA) binds to the high affinity receptor PLAUR
(UPAR) which is located on the leading edge of the migrating cells.
PLAUR (UPAR) associates on the cell surface with the
integrins of the beta(2)-integrin family, and with beta(1)- and beta(3)-integrins.
Binding of PLAUR (UPAR) with alpha-8/beta-1
integrin results in activation of PTK2 protein tyrosine kinase 2
(FAK1) that promotes phosphorylation of Breast cancer
anti-estrogen resistance 1 (p130CAS) protein.
Alpha-8/beta-1 integrin activates integrin-linked kinase
(ILK), which in turn phosphorylates V-akt murine thymoma
viral oncogene homolog 1 (AKT(PKB)) and activates
AKT(PKB)-dependent signaling pathways.
In multiple cells, binding of PLAU (UPA) to
PLAUR (UPAR) activates the Mitogen-activated protein kinase
1-3 (ERK1/2) pathway . After
PLAU (UPA) stimulation, integrins associate with
FAK1 and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene
homolog (c-Src) kinase. In
turn, c-Src activates the Epidermal growth factor receptor
(EGFR) that results in the recruitment of the SHC (Src
homology 2 domain containing) transforming protein 1
(Shc)/ Growth factor receptor-bound protein 2
(GRB2)/ Son of sevenless homolog
(SOS) to the activated receptor, thereby leading to v-Ha-ras
Harvey rat sarcoma viral oncogene homolog (H-Ras)
activation. Activated H-Ras activates the v-raf-1 murine
leukemia viral oncogene homolog 1 (c-Raf-1)/
ERK1/2 cascade .
EGFR serves as a critical adaptor protein in the pathway
that links PLAU (UPA) to
Upon activation of PLAUR (UPAR) by clustering, Janus
kinase 1 (JAK1) associates with the receptor, and Signal
transducer and activator of transcription 1 (STAT1) is
phosphorylated. Then STAT1 dimerizes, translocates from the
cytosol to the nucleus, where it binds to a specific DNA sites.
JAK1/STAT1 signal transduction
pathway including adaptor protein Interleukin 6 signal transducer
(gp130) is associated with PLAUR
Several specific inhibitors inactivate PLAU (UPA) on the
cell surface. These inhibitors include the PAI-1, the Serpin
peptidase inhibitor, clade B (ovalbumin), member 2 (PAI2),
the Serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1),
member 2 (SERPINE2) , and the Serpin
peptidase inhibitor, clade A (Protein C inhibitor) .
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