Biomedical Engineering Reference
In-Depth Information
1.4.1.1 Non-Enzymatic Roles of DP4 and FAP
In addition to their enzymatic roles, both DP4 and FAP exhibit a number of
important functions independent of their enzyme activity, many of which
involve binding with other proteins and indirect regulation of other proteases
such as matrix metalloproteinase (MMPs) and plasmin. Of particular ther-
apeutic interest are the non-enzymatic functions of DP4 and FAP that con-
tribute to their involvement in cell adhesion and migration. Both DP4 and
FAP interact with components of the extracellular matrix (ECM). The
observed roles of DP4 in adhesion and migration of cancer cells may be
attributable to its binding with cell surface fibronectin.
105
Notably, DP4 also
functions as a binding partner and adhesion molecule for other proteins
including adenosine-deaminase (DP4 is also known as ADA-binding
protein),
106,107
the kidney Na
1
/H
1
exchanger isoform NHE3,
108
and the
T-cell antigen CD45,
109
a protein tyrosine phosphatase. DP4 has also been
identified as a cell surface receptor for plasminogen.
110
DP4 binding with
ADA and CD45 initiates a signal transduction pathway via tyrosine phos-
phorylation contributing to the co-stimulatory effect of DP4 on T-cells.
73,111
Binding of the ADA-DP4 complex with plasminogen has been demonstrated
in 1-LN human prostate-cancer cell lines
112
and is thought to contribute to
FAP and DP4-mediated fibrinolysis.
61
Despite homology between the two
enzymes, no evidence exists for the binding of FAP with ADA.
91
In renal
brush-border membranes where the multimedia complex between DP4 and
Na
1
/H
1
exchanger isoform NHE3 is formed, inhibition of DP4 activity
results in the downregulation of NHE3 activity via inhibition of a tyrosine
kinase signaling pathway, thus suggesting that DP4 plays an important role in
modulating Na
1
H
1
exchange mediated by NHE3.
113,114
The exact mechan-
ism by which DP4 inhibitors affect downstream tyrosine kinase signaling
pathways is unknown, but it may be possible that inhibitor-binding results in
a conformational change to DP4, altering downstream signaling pathways or
that inhibition of DP4 activity prevents DP4 substrate-mediated signaling.
113
In the human 1-LN prostate-tumor cell line, it has been shown that the
association of plasminogen with DP4 and NHE3 is involved in regulating the
invasive phenotype.
115
Direct binding of plasminogen type II (Pg 2) with DP4
on the surface of prostate cancer cells results in the induction of an intra-
cellular Ca
21
signaling cascade that in turn results in the increased expression
of MMP9.
116
DP4-plasminogen binding is thought to 'lock' plasminogen into
a favorable configuration for its cleavage and activation by the urokinase
plasminogen activator receptor (uPAR).
110
It is this activation/interaction
with uPAR that results in release of intracellular calcium stores and induction
of MMP9 expression.
110
Interestingly, FAP is thought to interact directly
with uPAR via complex formation.
117
UPAR is an important cell surface
protease, converting plasminogen to plasmin, contributing to regulation of
ECM proteolysis.
118
Numerous studies have investigated physiological roles
and therapeutic potential of uPAR in human diseases such as cancer
(reviewed in several previous studies
119-121
). Co localization of FAP and
