Biomedical Engineering Reference
In-Depth Information
bond is important. DPP-4 is ubiquitously expressed and has numerous roles
throughout the body (Figure 5.1). These roles include:
An ability to rapidly inactivate the insulin-secreting hormones (incretins)
glucagon-like peptide-1 (GLP-1) and glucose insulinotropic peptide (GIP).
5
These hormones are important regulators of glucose metabolism. Specifi-
cally, inhibition of DPP-4 decreases cleavage and inactivation of these hor-
mones about 200-fold, thus allowing them to continue to stimulate insulin
release. This is the basis of DPP-4 targeting for type 2 diabetes therapy.
Potential cancer and disease marker. DPP-4 is dysregulated in chronic
liver disease.
6
It may be a marker for various cancers but, depending on
the cancer type, it is either upregulated
7-16
or downregulated
17
in the
cancer cells. DPP-4 as a serum biomarker is further complicated by the
diversity of conditions that alter serum levels.
Involvement in cell migration. DPP-4 also has extra-enzymatic functions
including binding fibronectin on rat hepatocytes
18
and breast- and lung-
cancer cells
19
independently of its enzyme activity.
3
This extra-enzymatic
ligand-binding ability plays a part in colonization and metastasis sug-
gesting a role for DPP-4 in breast-tumor progression.
20
Involvement in lymphocyte activation. DPP-4, also known as CD26, is
expressed by some resting T-cells. Activation of T-cells with antigen or
mitogens results in a five- to tenfold increase in CD26 expression, both in
the number of molecules per cell and the percentage of cells expressing
CD26.
21,22
The protease activity is not needed for soluble CD26-driven
human T-cell proliferation,
4
so the extra-enzymatic ligand-binding prop-
erties of CD26 probably contribute to its role in lymphocyte activation.
Participation in chemokine inactivation. DPP-4 enzyme activity has been
shown to cleave at least eight chemokines. The resultant DPP-4-cleaved
form of the chemokine can increase,
23-25
decrease,
26,27
or ablate
28-31
che-
motaxis, and increase
32
or decrease
24,26,33
chemoattraction, depending on
the chemokine upon which it acts. Stromal cell-derived factor-1a (SDF-1a)
is the only chemokine shown to be a physiological DPP-4 substrate.
34
Role in intestinal and renal hydrolysis and assimilation of prolyl pep-
tides.
35-37
DPP-4 is rate-limiting for hydroxyproline breakdown.
35
A role in apoptosis. DPP-4 over-expression in a number of cell lines
inhibits cell growth and increases apoptosis.
38-40
Interestingly, enzyme
activity is not required for these effects of DPP-4 over-expression in epi-
thelial and hepatic stellate cell lines.
3
5.2.2 Distribution of DPP-4
DPP-4 is widely distributed as a membrane-bound cell-surface dimeric pepti-
dase (amino acids 1-766) and also in a soluble form (amino acids 39-766)
found in extracellular fluids. Membrane-anchored DPP-4 is expressed by epi-
thelial cells including those in liver, gut, uterus, and kidney; by capillary
