REVIEW ARTICLE
The dipeptidyl peptidase IV family in cancer and cell
biology
Denise M. T. Yu
1
, Tsun-Wen Yao
1
, Sumaiya Chowdhury
1
, Naveed A. Nadvi
1,2
, Brenna Osborne
1
,
W. Bret Church
2
, Geoffrey W. McCaughan
1
and Mark D. Gorrell
1
1 A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Centenary Institute and Sydney Medical School, University
of Sydney, Australia
2 Pharmaceutical Chemistry, Faculty of Pharmacy, University of Sydney, Australia
Introduction
Proteases are heavily involved in specialized biological
functions and thus often play important roles in patho-
genesis. The dipeptidyl peptidase IV (DPIV ⁄ CD26)
gene family has attracted ongoing pharmaceutical
interest in the areas of metabolic disorders and cancer.
Four of its members – DPIV (EC 3.4.14.5), fibro-
blast activation protein (FAP), DP8 and DP9 – are

Of the 600+ known proteases identified to date in mammals, a significant
percentage is involved or implicated in pathogenic and cancer processes.
The dipeptidyl peptidase IV (DPIV) gene family, comprising four enzyme
members [DPIV (EC 3.4.14.5), fibroblast activation protein, DP8 and DP9]
and two nonenzyme members [DP6 (DPL1) and DP10 (DPL2)], are inter-
esting in this regard because of their multiple diverse functions, varying
patterns of distribution ⁄ localization and subtle, but significant, differences
in structure ⁄ substrate recognition. In addition, their engagement in cell bio-
logical processes involves both enzymatic and nonenzymatic capabilities.
This article examines, in detail, our current understanding of the biological
involvement of this unique enzyme family and their overall potential as
therapeutic targets.
Abbreviations
bFGF, basic fibroblast growth factor; DP, dipeptidyl peptidase; ECM, extracellular matrix; FAP, fibroblast activation protein; gko, gene
knockout; HSC, hepatic stellate cell; IL, interleukin; IP, interferon-c-inducible protein; IRAK-1, IL-1 receptor-associated serine ⁄ threonine
kinase I; ITAC, interferon-inducible T-cell chemo-attractant; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; NK,
natural killer; NPY, neuropeptide Y; SDF-1, stromal cell-derived factor-1; Th, T helper; uPAR, urokinase plasminogen activator receptor.
1126 FEBS Journal 277 (2010) 1126–1144 ª 2010 The Authors Journal compilation ª 2010 FEBS
and are therefore likely to play diverse roles. Some of
the functional significance placed on DPIV research
over decades is now being credited to the whole family,
particularly the newer members, DP8 and DP9, and so
modern selective DPIV pharmaceutical inhibitor design
has placed value on the structure and function of the
other DPs. The development and application of DPIV
inhibitors as successful type 2 diabetes therapeutics has
occurred over a relatively short period of time, in the
span of about a decade. Thus, careful consideration of
the biological properties of each DP is required in the
application of DP inhibitors to treat other disorders.

via protein–protein interactions [20], similarly to the
enzyme DP members that also have extra-enzymatic
abilities (Fig. 1).
Distribution of DPs in normal and
pathogenic tissue
DPIV distribution
DPIV is expressed by epithelial cells of a large number
of organs, including liver, gut and kidney; by endothe-
lial capillaries; by acinar cells of mucous and salivary
glands and pancreas; by the uterus; and by immune
organs such as thymus, spleen and lymph node [22–25]
(Fig. 2). Our recent study using the DPIV selective
inhibitor, sitagliptin, on wild-type and DPIV gene
knockout (gko) mouse tissue homogenates has con-
firmed the presence of DPIV enzyme activity in a large
number of organs [12].
DPIV is a potential marker for a number of cancers,
but with variability among different types of cancers.
DPIV is upregulated in a number of aggressive types
of T-cell malignancies, such as T-lymphoblastic
lymphomas, T-acute lymphoblastic leukaemias and
Cell type?
ECM environment?
Pro
DPi
DP ligand
Mechanism?
Enzymatic, extraenzymatic?
Effect of inhibitor?
Effect?

lated in lung adenocarcinoma [28], oesophageal adeno-
carcinoma [29], thyroid carcinoma [30–32], prostate
cancer [33] and B-cell chronic lymphocytic leukaemia
[34, 35], and dysregulated in liver cirrhosis [36]. How-
ever, DPIV expression is progressively downregulated
in endometrial adenocarcinoma [37]. Thus, some care
needs to be taken in the use of DPIV as a target for
different cancers. Further understanding of the biologi-
cal anti-invasive effect of DPIV in vitro could be of
importance in the control of certain carcinomas.
FAP distribution
The unique tissue distribution of FAP has made it a
potential marker and target for certain epithelial can-
cers. FAP is generally absent from normal adult tissues
[38]. In silico electronic northern blot analysis shows
that normal tissues generally lack FAP mRNA expres-
sion, with the exception of endometrium [39]. Also,
typing of cancers by electronic northern blotting
reveals predominant FAP signals in tumour types
marked by desmoplasia [39]. In vivo, FAP is generally
absent in normal adult epithelial, mesenchymal, neural
and lymphoid cells [40], or in nonmalignant tumours,
such as fibroadenomas, and in nonproliferating fibro-
blasts [38]. Nevertheless, a soluble form of FAP has
been isolated from bovine serum [41] and from human
plasma [42,43]. FAP expression is highly induced dur-
ing inflammation, for example, within fibroblast-like
synovial cells in rheumatoid arthritis and osteoarthritis
[44,45]. FAP is also significantly upregulated at sites of
tissue remodelling, such as the resorbing tadpole tail

antibody targeting [53–55], FAP DNA vaccination
[56], immunotherapy [57] and inhibitor therapies [58].
It is not yet clear whether inhibiting FAP enzyme
activity alone can lead to anti-tumorigenic effects
(Fig. 1), although the use of FAP enzyme-inactive
mutants in tumour growth studies have supported this
concept [59]. Recent alternative approaches that utilize
or localize FAP enzyme activity have shown potential,
including a FAP-activated promelittin protoxin that
reduces tumour growth in mice [60], and a FAP-trig-
gered photodynamic molecular beacon for the detec-
tion and treatment of epithelial cancers [61].
DP8 and DP9 distribution
The distribution of DP8 and DP9 has been studied by
our group in some depth. Ubiquitous DP8 and DP9
mRNA expression was previously shown by a Master
RNA dot-blot [62] and a multiple-tissue northern blot
[8,9]. More recently, we confirmed ubiquitous expres-
sion using enzyme assays in the presence of a DP8 ⁄ 9
inhibitor, in situ hybridization and immunohistochem-
istry, particularly in immune cells, epithelia, brain,
testis and muscle [12]. DP8 and DP9 enzyme levels are
predominant over DPIV in mouse testis and brain.
In situ hybridization and immunohistochemistry analy-
ses on baboon and human tissues detected DP8 and
DP9 in lymphocytes and epithelial cells in the gastroin-
testinal tract, skin, lymph node, spleen, liver and lung,
as well as in pancreatic acinar cells, adrenal gland,
spermatogonia and spermatids of testis, and in Pur-
kinje cells and in the granular layer of cerebellum. The

ries, namely enzymatic and extra-enzymatic (protein–
protein interactions) (Fig. 1). The enzymatic roles
relate to the substrates of the DPs, whereas the
extra-enzymatic roles relate to their ligand-binding
properties.
DPIV
Enzymatic activity of DPIV and its role in type 2
diabetes
The ubiquitously expressed enzymatic action of DPIV
covers a large range of physiological substrates
involved in varied functions. DPIV is best known
for its enzymatic ability to inactivate the incretin
hormones glucagon-like peptide-1 and glucose insuli-
notropic peptide. In the treatment of type 2 diabetes,
DPIV inhibitors extend incretin action, resulting in
improved glucose metabolism via prolonged insulin
release and trophic beta cell effects [72,73]. We have
discussed this therapeutic application of DPIV inhibi-
tors elsewhere [74].
Other physiological substrates of DPIV include neu-
ropeptide Y (NPY), substance P and the chemokine
stromal cell-derived factor-1 (SDF-1 ⁄ CXCL12). NPY
is involved in the control of appetite, energy homeosta-
sis and blood pressure [75]. DPIV-truncated NPY is
unable to bind to its Y1 receptor, instead binding to
its Y2 and Y5 receptors, which promote angiogenesis
[75] and inflammation [76]. Substance P, involved in
pain perception and nociception, is inactivated by
DPIV enzyme activity [77]. DPIV enzyme activity is
effective on a number of chemokines in vitro (Table 2).

(ECM)-coated plastic, and exhibited increases in both
spontaneous and induced apoptosis [50]. Wesley et al.
[90–93] found that DPIV overexpression in a number
of cell lines (melanocytes, nonsmall cell lung, prostate
and neuroblastoma cancer lines) caused anti-tumori-
genic effects, such as inhibition of in vitro cell migra-
tion and cell growth, increased apoptosis and
inhibition of anchorage-independent growth. Other
studies have confirmed similar findings in melanoma
cells and in ovarian carcinoma cells [94,95]. In vivo,
nude mice injected with DPIV-overexpressing cancer
cells showed inhibition of tumour progression
compared with control cancer cells [91,93].
A number of signalling pathways have been associ-
ated with DPIV ECM interactions, including the basic
fibroblast growth factor (bFGF) pathway, which is
involved in cell proliferation, migration, cell survival,
wound healing, angiogenesis and tumour progression.
Overexpression of DPIV in prostate cancer cells blocks
the nuclear localization of bFGF, lowers bFGF levels
and subsequently affects downstream components of
the bFGF pathway [mitogen-activated protein kinase
(MAPK)-extracellular signal-regulated kinase 1 ⁄ 2 and
urokinase plasminogen activator]. These changes are
accompanied by the induction of apoptosis, cell cycle
arrest and the inhibition of in vitro cell migration [92].
Sato et al. [96] have shown that DPIV mediates cell
Table 2. Potential downstream effects of DPIV on chemokines.
Chemokine Cell type Activity of DPIV-cleaved form Reference
Gro b

ablates chemotaxis of activated
Th1 lymphocytes
[169,170]
ITAC
f
(CXCL11) Expressed by leucocytes, fibroblasts,
endothelial cells, pancreas, liver
astrocytes Acts on activated T cells
loss of Ca
2+
flux via CXCR3
less chemotaxis of activated Th1
and NK cells
[168,171]
SDF-1
g
(CXCL12) Acts on lymphocytes, dendritic cells,
haematopoetic cells
less tumour growth
less lymphocyte chemotaxis
ablates antiviral activity
more chemoattraction of monocytes
regulation of haematopoietic stem
cell recruitment
[131,172,173]
LD78b (CCL3 ⁄ L1) Expressed by T cells, B cells and monocytes more chemoattraction of monocytes [174]
Eotaxin (CCL11) Acts on eosinophils, basophils, Th2 lymphocytes less chemotaxis of eosinophils
less binding ⁄ signalling via CCR3
[170,175,176]
MDC

1130 FEBS Journal 277 (2010) 1126–1144 ª 2010 The Authors Journal compilation ª 2010 FEBS
adhesion to the ECM via p38 MAPK-dependent phos-
phorylation of integrin b
1
. Inhibition of DPIV expres-
sion using small interfering RNA in the T-anaplastic
large cell lymphoma cell line Karpas 299 causes reduc-
tion of adhesion to fibronectin and collagen I. Also,
DPIV-depleted Karpas 299 cells have reduced tumori-
genicity compared with control Karpas 299 cells when
injected into severe combined immunodeficient mice
[96]. This finding contrasts that observed by Wesley
et al., possibly reflecting cell-type differences. In the
Burkitt B-cell lymphoma line, Jiyoye, DPIV overex-
pression results in increased phosphorylation of p38
MAPK but no accompanying increase in cell adhesion
[96,97]. DPIV overexpression in neuroblastoma lines
leads to induction of apoptosis mediated by caspase
activation, and downregulation of the chemokine
SDF-1 and its receptor CXCR4. SDF-1 downregula-
tion, in turn, leads to induced cell migration and to
decreased levels of phospho-Akt and active MMP-9
[93]. Other molecules that are upregulated by DPIV
overexpression include p21, CD44 [50,91], topoisomer-
ase IIa [97] and the known cell-adhesion molecules
E-cadherin and tissue inhibitor of matrix metallopro-
teinases [50,98].
DPIV in immune function
Also known as CD26 T-cell differentiation marker,
DPIV plays vital roles in immunology and autoimmu-

[111–113]. Through its expression on T cells, CD26 is
able to provide a costimulatory signal in lipid rafts
[80,114,115] to augment the T-cell response to foreign
antigens [109,116,117] (Fig. 3). Crosslinking of CD26
with antibody increases the recruitment of CD26 and
CD45 to these rafts [80] and induces T-cell activation
[113,118]. The signal transduced by CD26 overlaps
with the T-cell receptor ⁄ CD3 pathway, increasing tyro-
sine phosphorylation of p56
lck
, p59
fyn
, ZAP-70, phos-
pholipase C-c, MAPK and c-Cb1 in that pathway
[119,120]. CD26 on activated memory T cells binds to
caveolin-1 on antigen-presenting cells at the immuno-
logical synapse for T cell ⁄ antigen-presenting cell inter-
actions [81]. Stimulation of CD26 also causes IL-1
receptor-associated serine ⁄ threonine kinase I (IRAK-1)
and Toll-interacting protein to disengage from caveo-
lin-1. IRAK is phosphorylated in this process, which
leads to the upregulation of CD86 expression [121].
The interaction between CD26 and caveolin-1 also
leads to the recruitment of lipid rafts, which are impor-
tant for modulating signal transduction. Additional
recruitment of a complex including CARMA1 in lipid
rafts leads to events downstream of the T-cell receptor
complex to activate the nuclear factor-jB pathway
[82].
Thus, the role of CD26 in lymphocyte activation is

tions by CD8
+
T cells [109,127,128] and is also upreg-
ulated in activated B cells [34,129,130]. CD26
overexpression in a B-cell line enhances p38 phosphor-
ylation, suggesting that as in T cells, CD26 in B cells
could be involved in the MAPK p38 signalling
pathway to activate signaling molecules such as extra-
cellular signal-regulated kinase, p56
lck
, p59
fyn
, ZAP-70,
c-Cbl and phospholipase C-c [97,119].
CD26 has nine chemokine substrates in vitro:
eotaxin (CCL11), macrophage-derived chemokine
(CCL22), growth-regulated protein b (CXCL2),
LD78b (CCL3 ⁄ L1), granulocyte chemotactic protein 2
(CXCL6), monokine-induced interferon-c (CXCL9),
interferon-c-inducible protein (IP-10 ⁄ CXCL10), inter-
feron-inducible T-cell chemo-attractant (ITAC⁄ CXCL
11) and SDF-1 (CXCL12) (Table 2). Of these, SDF-1
is the only verified chemokine substrate in vivo [131].
By enzyme cleavage, CD26 reduces the inflammatory
properties of these chemokines by altering or abrogat-
ing the ability to trigger a signal via the cognate recep-
tors, and in some cases the cleaved chemokine also
blocks binding by the corresponding intact chemokine
molecule.
FAP

neous and induced apoptosis [50]. Overexpression of
FAP in melanoma cells leads to suppression of the
malignant phenotype in cancer cells, specifically cell
cycle arrest at the G0 ⁄ G1 phase, increased suscepti-
bility to stress-induced apoptosis and restoration of
contact inhibition [136]. Overexpression of FAP
abrogates tumorigenicity in nude mice; surprisingly,
enzymatically inactive FAP further abrogates
tumorigenicity [136].
In contrast to the above described anti-tumorigenic
effects, FAP-overexpressing HEK293 cells, when xeno-
grafted into severe combined immunodeficient mice,
result in a significantly greater incidence of tumour
development and growth compared with controls,
including an enzyme-inactive mutant [59,137]. FAP
overexpression in the hepatic stellate cell line, LX-2,
enhances adhesion and migration on collagen and
fibronectin on ECM substrata in vitro [50]. These data
suggest that FAP has a critical role in liver fibrosis,
probably by influencing the functions of activated
hepatic stellate cells and ⁄ or by interacting with the
ECM. FAP expression is stimulated by transforming
growth factor-b and retinoic acid, which also
stimulate HSC and myofibroblasts [134]. Moreover,
transforming growth factor-b1 is a major stimulus for
epithelial–mesenchymal transition, a contributor of
myofibroblasts in chronic liver injury [138].
DP8 and DP9
DP8 and DP9 have no confirmed physiological
substrates, but do have the ability to cleave the DPIV

be mammalian H
2
O
2
-sensing proteins that are impor-
tant in intracellular processes where H
2
O
2
is regulated,
such as phosphorylation, signaling pathways, apopto-
sis, cancer and immune function [141–144]. While
DP9, but not DP8, overexpression is associated with
spontaneous apoptosis, both elevate induced apoptosis.
Apoptosis is an important process in tissue remodel-
ling, including recovery from liver injury [145]. At a
biochemical level, apoptosis is a complex cellular event
involving the coordinated action of proteins, several
different peptidases, nucleases and membrane-associ-
ated ion channels and phospholipid translocases. As
DP8 and DP9 activities are dependent on the redox
state of their cysteines, the redox states of DP8 and
DP9 may be a molecular switch in the regulation of
apoptotic pathways [140]. In addition, as cytoplasmic
DPIV can be phosphorylated [146], DP8 and DP9 may
also be phosphorylated in signalling pathways, and, in
fact, phosphorylation sites in DP8 and DP9 are identi-
fiable using the NetPhos server [147].
Studies involving the use of nonselective CD26
inhibitors in CD26-deficient systems suggest that DP8

oxygen species responsiveness of DP8 and DP9 enzyme
activities may have an involvement in apoptosis
induction of activated T cells [141].
Insights of DP biological functions
from DP-deficient animals
DPIV gko and FAP gko mice are healthy. Moreover,
DPIV gko mice have increased glucose clearance after
a glucose challenge, compared with wild-type
mice [154]. The same effect is found with DPIV-inhibi-
tor-treated wild-type mice, but not with DPIV-inhibi-
tor-treated DPIV-deficient mice, showing that the
mechanism is DPIV enzyme-activity dependent. DPIV
gko mice resist diet-induced obesity and associated
insulin resistance, probably through the activation of
peroxisome proliferator-activated receptor-a, which is
involved in fatty acid oxidation, downregulation of ste-
rol regulatory element-binding protein-1c (which is
involved in lipid synthesis) and reduced appetite [155].
DPIV-deficient animals also appear to have a mildly
altered lymphocyte phenotype. DPIV gko mice have a
decreased number of natural killer (NK) T lympho-
cytes in peripheral blood, suggesting that DPIV may
be involved in the development, maturation and migra-
tion of NK T cells [130]. Moreover, NK cell cytotoxic-
ity against breast adenocarcinoma cells has been found
to be decreased in CD26-deficient rats, suggesting that
DPIV activity is associated with NK cytotoxicity [156].
Studies on the DPIV-deficient Fischer rat have shown
Denise M. T. Yu et al. DPIV family in cancer and cell biology
FEBS Journal 277 (2010) 1126–1144 ª 2010 The Authors Journal compilation ª 2010 FEBS 1133

mice suggests that targeting either or both enzymatic
and extra-enzymatic functions of DPIV and FAP is
likely to produce few, if any, additional off-target
effects. It appears that either all roles of DPIV and
FAP in vivo are not critical, or perhaps that compensa-
tory upregulation of another DP occurs in their
absence, or both. Our enzyme distribution study sug-
gests that in some DPIV gko mouse organs, a DP
activity was detected that is probably not DP8 ⁄ 9
derived, but is present at low levels [12]. The adjacent
position of the DPIV and FAP genes causes a DPIV ⁄
FAP double knockout mouse to be very difficult to
generate, and DP8 and DP9 knockout animals have
not been reported.
Implications for DPs in cell biology and
cancer targeting
Overall, there appears to be evidence for both extra-
enzymatic and enzymatic functions of DPs in cell biol-
ogy. The two functions may work synergistically, in
opposition or even independently, depending on the
microenvironment and cell type. In many overexpres-
sion studies, similar effects have been found with both
enzyme-inactive DP mutants and wild-type DP.
However, a change in expression level of a DP in
response to a stimulus is likely to have downstream
enzymatic effects; for instance, in neuroblastoma cell
lines, SDF-1-mediated migration is attenuated in the
presence of overexpressed DPIV [93].
There has been some interest in the use of DP inhib-
itors for cancer therapy. The nonselective DP inhibi-

sion is variable in cancers, being upregulated in certain
cancer types and downregulated in others. As DPIV
and FAP have multifunctional properties, their expres-
sion levels and mechanisms or sites of action in various
cell types may depend on the particular requirement of
the cell and on the surrounding environmental factors
at any given time (Fig. 1). This seems to be the case
for a number of proteases [71].
Structure of the DPIV gene family
proteins and therapeutic considerations
There are a number of favourable factors in consider-
ing the design and application of DP inhibitors in
DPIV family in cancer and cell biology Denise M. T. Yu et al.
1134 FEBS Journal 277 (2010) 1126–1144 ª 2010 The Authors Journal compilation ª 2010 FEBS
therapeutics. First, the relatively small size of the
enzyme family can make it easier to specifically target
the enzyme of interest and distinguish it from other
members of the family. Second, as indicated by the
phenotype of the gko mice, neither the enzymatic nor
the extra-enzymatic roles of DPIV and FAP appear to
play critical survival roles, which reduces the likelihood
of side effects. Third, although similar in structure, the
DPs have some differences at their active site
[3,140,162], so it is likely that individual DPs can be
specifically targeted through careful drug design.
Fourth, although they have overlapping properties, the
DPs appear to play different roles to each other
in vivo. This is apparent by differences in their distri-
bution [12] and in vitro biological effects [13,50], and
in the absence of compensatory upregulation of DP8

regions around the active site include two loop regions
– one forming the P2 pocket (P2-loop) and the other
forming a substrate-binding region connected to the
glutamate-rich region (EE-helix) and stabilized by salt
bridges (R-loop) [162,164]. Analysis of the crystal
structures of DPIV, FAP and DP6, and of the models
of DP8 and DP9, indicate that the R-loop is ideal for
selectivity and provides a structural basis for the
design of enzyme-selective inhibitors [162]. At present
a number of DP8 ⁄ 9 selective inhibitors have been
A
B
Fig. 4. Ribbon representation of the sitagliptin-bound DPIV mono-
mer (PDB ID 1X70). (A) Variable and conserved structural features
of the DPIV gene family proteins. The C-terminal a ⁄ b-hydrolase
domain and the b-propeller domain are coloured blue and grey
respectively. The DPIV inhibitor sitagliptin (shown as a green stick)
denotes the location of the active site. Some residues in front of
the figure, which would otherwise obscure the active site, have
been omitted to indicate the hollow cavity found in this protein
family. The regions of the active site are represented as follows:
the catalytic triad Ser, Asp and His (conserved region) as magenta,
grey and blue spheres, respectively; the P2-loop (variable region) in
cyan; the R-loop (variable region) in dark green; and the glutamate-
rich EE-helix (conserved) in red [162]. The double-glutamate motif
is shown as red spheres. The yellow sphere denotes the acidic
region caused by the presence of Asp663 in DPIV (conserved in
DP8 and DP9, equivalent to Ala657 in FAP). (B) Close-up view of
the sitagliptin-bound active site of DPIV. Sitagliptin is shown in stick
representation, with carbon in green, nitrogen in blue, oxygen in

valuable to assess in detail the individual distribution
and localization of each DP, the cell type of interest,
structure–function relationships and the balance
between extra-enzymatic and enzymatic properties, as
well as their overall contribution to biological pro-
cesses.
Acknowledgements
The authors thank Lingsi Lu for graphics services,
Ana Julia Vieira de Ribeiro for critical reading and the
National Health and Medical Research Council of
Australia for a postgraduate scholarship to DMTY
and grants to MDG and GWM. TWY and NAN hold
Australian Postgraduate Awards.
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