Báo cáo khoa học: The dipeptidyl peptidase IV family in cancer and cell biology pot

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

characterized by a rare enzyme activity, namely hydro-
lysis of a prolyl bond two residues from the N-termi-
nus. DPIV is the best-studied member of the family
and has a variety of roles in metabolism, immunity,
endocrinology and cancer biology. DPIV is a new and
successful type 2 diabetes therapeutic target, and FAP
is under investigation as a cancer target. Although the
exact functions of the newer members, DP8 and DP9,
are yet to be elucidated, thus far they have been found
to have interesting biological properties and, like DPIV
and FAP, are likely to be multifunctional and employ
both enzymatic and extra-enzymatic modes of action.
Although DPIV, FAP, DP8 and DP9 possess similar
enzyme activity and are structurally conserved, they
have varying patterns of expression and localization
Keywords
cancer; dipeptidyl peptidase; distribution;
enzyme; extracellular matrix; immune
function; liver fibrosis; structure
Correspondence
M. D. Gorrell, Molecular Hepatology,
Centenary Institute, Locked Bag No. 6,
Newtown, NSW 2042, Australia
Fax: +61 2 95656101
Tel: +61 2 95656156
E-mail:
(Received 23 October 2009, revised 25
November 2009, accepted 30 November
2009)
doi:10.1111/j.1742-4658.2009.07526.x

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.

The DPIV gene family
The DPIV gene family is a subgroup of the prolyl
oligopeptidase family of enzymes (Table 1), which are
specialized in the cleavage of prolyl bonds. As most
peptide hormones and neuropeptides comprise one or
more proline residues, this family of enzymes is useful
for processing and degrading such peptides [1,2].
DPIV and FAP (also known as seprase) are closely
related cell-surface enzymes, with DPIV-like enzyme
activity. FAP is also a narrow-specificity endopeptidase
[3–5]. FAP endopeptidase activity includes a type I col-
lagen-specific gelatinase [6,7] activity and seems
restricted to Gly-Pro-containing substrates [4], which is
interesting because the DP activity of FAP is greater
on H-Ala-Pro than on H-Gly-Pro-derived artificial
substrates [3].
DP8 and DP9 are dimers with DPIV-like enzyme
activity [8–11]. Although DP8 and DP9 are very clo-
sely related to each other and share similar distribution
patterns [12], there are some differences in their cell
biological effects (discussed later), perhaps related to
their cytoplasmic localization, and so may play differ-
ent roles [13].
The nonenzymatic members of the family – DP6
(DPL1 ⁄ DPX) and DP10 (DPL2 ⁄ DPY) – are modula-
tors of voltage-gated potassium channels in neurons
and are primarily expressed in brain [14–18]. Although
structurally similar to DPIV [19,20], they lack the cata-
lytic serine and other residues necessary for enzyme
activity [17,21]. Thus, they are likely to exert effects

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?

Protumorigenic or
Anti-tumorigenic?
Regulatory processes?
Fig. 1. Dynamics involved in DP biology. The DPs have both enzy-
matic and extra-enzymatic properties, and the outcomes of their
action may lead to anti-tumorigenic or tumorigenic effects, depend-
ing on factors such as cell type, regulation and microenvironment.
Table 1. Criteria and subclans of the prolyl oligopeptidase (POP;
EC 3.4.21.26) family of enzymes (MEROPS –the Peptidase Data-
base; merops.sanger.ac.uk; [166]).
Criteria for POP family members
DNA sequence homology to prolyl endopeptidase (PEP ⁄ POP)
Subclans of the POP family
S9A Prolyl endopeptidase (PEP ⁄ POP)
S9B Dipeptidyl peptidase IV (DPIV)
S9C Acylaminoacyl peptidase
S9D Glutamyl endopeptidase (plant)
S9B subclan - DPIV gene family
DPIV
Fibroblast activation protein (FAP)
DP8
DP9
Nonenzyme DPIV-related POP family members
DP6 (DPX, DPL1)
DP10 (DPY, DPL2)
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 1127
T-anaplastic large cell lymphomas [26], and is a mar-
ker of poor prognosis for T-large granular lymphocyte
lymphoproliferative disorder [27]. DPIV is also upregu-

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

[46], during scar formation in wound healing [38] and
at sites of tissue remodelling during mouse embryogen-
esis, including somites and perichondrial mesenchyme
from cartilage primordia [47].
In addition, FAP is preferentially expressed by acti-
vated, but not by resting, hepatic stellate cells (HSCs)
of cirrhotic liver, but not in normal human liver [6].
FAP-immunopositive cells are present in the early
stages of liver injury, and the expression level of FAP
mRNA correlates with the histological severity of
fibrosis in chronic liver diseases [48]. FAP co-localizes
with fibronectin and collagen in cirrhotic liver, with
collagen fibrils present alongside activated HSCs
[49,50]. FAP is expressed only by myofibroblasts and
activated HSCs at sites of tissue remodelling, which is
the portal–parenchymal interface of cirrhotic liver [6].
FAP is upregulated in most human cancers [51].
FAP is highly expressed by fibroblasts at the remodel-
ling interface in human idiopathic pulmonary fibrosis
[52]. Interestingly, FAP is highly upregulated on reac-
tive stromal fibroblasts of over 90% of human epithe-
lial tumours, but not in benign tumours [38]. As
stromal fibroblasts are a common feature of epithelial
cancers, including breast, colorectal, ovarian and lung
carcinomas, FAP is a potential therapeutic target for
Fig. 2. Overview of the distribution of the DPs in normal and pathogenic tissue and cell types.
DPIV family in cancer and cell biology Denise M. T. Yu et al.
1128 FEBS Journal 277 (2010) 1126–1144 ª 2010 The Authors Journal compilation ª 2010 FEBS
multiple human epithelial cancers [38]. Previous FAP-
specific cancer therapeutic investigations have included

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

results of other studies are in agreement with these
findings [63–66]. The significance of the three DP8
splice variants is not known [8,67]; however, one of the
splice variants is upregulated in human adult testis
compared with fetal testis [67]. There are two known
DP9 transcripts – a ubiquitously expressed transcript
of 863 amino acids [9,68,69] and a larger 971-amino
acid transcript in muscle, spleen and peripheral blood
leukocytes [9]. The larger form appears to be expressed
in tumours [9].
There is some early evidence suggesting that DP8
and DP9 expression may be associated with disease
pathogenesis. The DP9 mRNA levels are elevated in
testicular tumours [12] and DP9 has also been shown
to be upregulated in DNA arrays comparing nontu-
mour and normal liver tissue [70]. In diseased liver,
DP8 and DP9 mRNA has been detected in infiltrating
lymphocytes [12]. DP8 ⁄ 9 expression is higher in
inflamed lung, probably also associated with activated
lymphocytes [63]. These distribution patterns, as well
as DP inhibitor studies (see a later section), support
possible roles for DP8 and DP9 in inflammation and
in the immune system.
Biological functions of DPIV, FAP and
DP8/9
The DPs have interesting roles in cell biology and in
pathogenic processes. DPIV and FAP have been iden-
tified both as potential cancer markers and as prote-
ases with anti-tumorigenic properties [71]. Their
mechanisms of action generally fall into two catego-

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).

DPIV in cell biology
A number of DPIV-binding proteins have been identi-
fied, including adenosine deaminase [78,79], CD45
(protein tyrosine phosphatase) [80], caveolin-1 [81],
CARMA1 [82], fibronectin III [83,84], plasminogen 2
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 1129
[85], Na
+
-H
+
exchanger isoform 3 [86] and glypican-3
[87]. Adenosine deaminase, CD45, caveolin-1 and
CARMA1 are involved in the costimulation of T cells
by DPIV, whereas fibronectin III, plasminogen 2 and
glypican-3 may have roles in cancer biology. Binding
of DPIV to fibronectin III is important for metastasis
and colonization of breast cancer cells, implicating the
role of DPIV in tumour progression [88]. In the
human prostate tumour 1-LN cell line, direct binding
of plasminogen 2 with cell-surface DPIV induces a sig-
nal transduction cascade that produces a rapid increase
in the calcium ion concentration, subsequently result-
ing in the expression of matrix metalloproteinase 9
(MMP-9), which enhances the invasiveness of cells
[89].
Overexpression of DPIV in cell lines results in inter-
esting cell-behavioural effects. Our studies have found
that 293T epithelial cells transfected with DPIV
exhibited less cell migration on extracellular matrix

(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

a
(CXCL2) Acts on neutrophils and basophils unknown [139]
GCP2
b
(CXCL6) Acts on neutrophils no difference in chemotaxis of
neutrophilic granulocytes
[167]
MIG
c
(CXCL9) Expressed by stimulated monocytes,
macrophages and endothelial cells.
Acts on Th1
d
lymphocytes
ablates chemotaxis of activated
Th1 lymphocytes
[168]
IP10
e
(CXCL10) Expressed by neutrophils, hepatocytes,
endothelial cells, keratinocytes. Acts on
CD4
+
T cells, haematopoetic progenitor
cells, lymphocytes
less chemoattraction CD4
+
T cells
inhibits haematopoetic progenitor
proliferation

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

h
(CCL22) Acts on NK cells, T-cell subsets, monocytes,
dendritic cells
ablates chemotactic activity for
lymphocytes less Ca
2+
mobilization
via CCR4
[168,177,178]
a
Gro b, growth regulated protein b;
b
GCP, granulocyte chemotactic protein;
c
MIG, monokine-induced interferon-c;
d
Th, T helper;
e
IP10,
interferon-c-inducible protein 10;
f
ITAC, interferon-inducible T-cell chemo-attractant;
g
SDF-1, stromal cell-derived factor 1;
h
MDC, macro-
phage-derived chemokine;
i
NK, natural killer.
DPIV family in cancer and cell biology Denise M. T. Yu et al.

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-

nity [99]. It is expressed at detectable levels by some
resting T cells, but the cell-surface expression increases
by 5 to 10-fold following stimulation with antigen,
anti-CD3 plus interleukin (IL)-2 or mitogens such as
phytohaemagglutinin [25,100–105]. The strongest lym-
phocytic CD26 expression is found on cells co-express-
ing high densities of other activation markers, such
as CD25, CD71, CD45RO and CD29 [106–108]. The
CD26
bright
CD4
+
population of T cells is the
CD45RO
+
CD29
+
memory ⁄ helper subset, which
responds to recall antigens, induces B-cell IgG synthe-
sis and activates cytotoxic T cells [102,107,109]. In
addition, CD26
bright
CD4
+
memory T cells preferen-
tially undergo transendothelial migration [108,110].
CD26 has a costimulatory role in T-cell activation
and proliferation. CD26 is mainly expressed on T
helper (Th) 1 cells and its expression is induced by
stimuli favouring the development of Th1 responses

[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

probably attributable to its extra-enzymatic ligand-
binding properties, as further evidenced by in vitro
studies. Stimulation with a combination of anti-CD3
and anti-CD26 IgGs induces more IL-2 production by
Fig. 3. Features of the effects of DP upon T-cell activation ⁄ func-
tion. Cell-surface CD26 ⁄ DPIV interacts with adenosine deaminase,
CARMA-1 and caveolin-1. Stimulation of CD26 causes IRAK-1 and
Toll-interacting protein to disengage from caveolin-1, resulting in
the phosphorylation of IRAK-1 and the upregulation of CD86
expression. Interaction with caveolin-1 also results in the recruit-
ment of lipid rafts, leading to events downstream that activate the
nuclear factor-jB pathway. The roles of intracellular DP8 and DP9
in lymphocyte proliferation are likely to be enzymatic, in contrast to
the role of DPIV, and they may modulate signalling molecules.
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 1131
CD26-transfected Jurkat cells than by CD26 enzyme-
negative mutant transfected cells [116], suggesting that
the proteolytic activity of CD26 is not essential in the
costimulatory function of CD26. Moreover, soluble
CD26 enhances the proliferation of activated periph-
eral blood lymphocytes by decreasing strong responses
and increasing weak responses of T cells [122,123].
Studies involving CD26 enzyme-deletion mutants have
shown that the costimulatory activity of CD26
involves the ligand-binding domain [124,125]. A recent
in vivo study using a DPIV-selective inhibitor in DPIV
gko mice has further shown independence of immune
functions of CD26 from its enzyme activity [126].
CD26 has a role in the development of effector func-

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

The endopeptidase activity of soluble FAP cleaves
a2-antiplasmin [42,43, 132], which is involved in blood
clotting. The gelatinase activity of FAP is likely to be
associated with its expression in ECM remodelling.
One putative FAP ligand, urokinase plasminogen acti-
vator receptor (uPAR), has been reported in LOX
malignant melanoma cells [133,134]. Because the
uPAR ligand, urokinase plasminogen activator, is able
to convert plasminogen to plasmin, which degrades
fibrin and certain ECM proteins, formation of the
heterogeneous proteolytic complex between FAP and
uPAR might enhance the invasive and metastatic abili-
ties of tumour cells [133,134].
FAP expression is associated with normal or exces-
sive wound healing, and with malignant tumour
growth and chronic inflammation [38], including
human liver cirrhosis [6]. All of these processes involve
ECM degradation. Proteolytic degradation of ECM
components facilitates angiogenesis and ⁄ or tumour cell
migration. Many proteases, including secreted and cell-
surface metalloproteinases, and some serine peptidases,
have roles in these processes. The gelatinase activity of
FAP, specifically collagenolytic activity towards type I
collagen fragments, suggests that FAP could in this
way contribute to ECM degradation [6,7,135].
Like DPIV, overexpression of FAP frequently
leads to anti-tumorigenic effects. In overexpression
studies using the HEK293T epithelial cell line, FAP
had decreased adhesion on collagen I, fibronectin
and Matrigel, and exhibited increases in both sponta-

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

substrates glucagon-like peptide-1, glucagon-like
peptide-2, NPY and peptide YY in vitro [11,65]. In
addition, DP8 can cleave four chemokines [139]. No
ligands of DP8 and DP9 have been reported.
DPIV family in cancer and cell biology Denise M. T. Yu et al.
1132 FEBS Journal 277 (2010) 1126–1144 ª 2010 The Authors Journal compilation ª 2010 FEBS
DP9 overexpression studies in the HEK293T epithe-
lial cell line have revealed roles for DP9 in cell adhe-
sion, in in vitro wound healing, in cell migration, and
in proliferation and apoptosis, and roles for DP8 have
been found in wound healing, in cell migration and in
apoptosis enhancement [13]. DP9 overexpression
impaired cell behaviour on a wider range of ECM
components than for DP8. Despite their close sequence
relatedness, DP8 and DP9 exert some differences in
their cellular effects. Therefore, these two proteins are
likely to have different functions and ligands.
The mechanism of action of intracellular DP8 and
DP9 remains unknown. Many cytoplasmic events are
involved in cell–ECM interactions, causing changes to
cell behaviour, so it is difficult to predict which events
are influenced by cytoplasmic DP8 and DP9. The
observed decreases in DP9-overexpressing cells of the
ECM-interacting molecules discoidin domain receptor
1, a kinase activated by collagen binding, and the
MMP inhibitor, tissue inhibitor of matrix metallopro-
teinase-2, suggest possible DP9 target pathways [13].
The discovery of DP8 and DP9 as reactive oxygen
species-responsive molecules may provide an indication
of a cytoplasmic function [140]. DP8 and DP9 might

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

and DP9 are likely to play immune roles previously
attributed to CD26, for example, in in vitro prolifera-
tion [148], arthritis [149] and haematopoiesis [150].
Recently, there has been more direct evidence of DP8
and DP9 immune function, and their potential as tar-
gets for inflammatory diseases. As previously outlined,
DP8 and DP9 are present in leucocytes and leucocyte
cell lines [8,12,151]; DP8 mRNA is upregulated in
asthma-induced lung [63]; and an inhibitor of DP8 and
DP9 attenuates T-cell proliferation [152] and sup-
presses DNA synthesis in mouse splenocytes from both
wild-type and DPIV gko mice [153].
The use of inhibitors in these studies has suggested
that while the CD26 immune system function appears
to be extra-enzymatic, DP8 and DP9 immune func-
tions appear to be enzymatic, although the mecha-
nisms are yet to be elucidated. We have reported four
chemokine substrates of DP8 in vitro, namely SDF-1a,
SDF-1b, IP10 and ITAC [139], although it is unclear
whether intracellular DP8 makes physical contact with
chemokines in vivo. DP8 could potentially be released
to the extracellular space upon cell death in inflamma-
tory lesions, whereby it could retain its activity and
process chemokines involved in these pathological
lesions [139]. In addition, IP10 and ITAC have crucial
roles in hepatitis C virus infection, and DP8 is
expressed in B-cell chronic lymphocyte leukaemia, var-
ious tumours and activated T cells [9]. This selective
chemokine inactivation might have implications for
cancer biology and immunobiology. The reactive

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

age-dependent alteration of thymic emigration patterns
and leucocyte subsets [157]. A recent report in DPIV
gko mice treated with a DPIV-selective inhibitor dem-
onstrated that DPIV selective inhibition does not
impair T-dependent immune responses to antigenic
challenge [126].
The FAP gko mouse has a normal phenotype in his-
tological and haematological analysis [158], and the
lack of FAP expression does not impair development
or tissue remodelling in embryos [47]. Therefore, other
compensatory pathways are likely to exist involving
molecules with functions similar to FAP, which could
include other DPIV family members or MMPs. Studies
on tissue-remodelling models of FAP gko mice may
help to elucidate its roles, in greater detail, in extra-
cellular matrix interactions, liver fibrosis and cancer.
Our studies have indicated that FAP gko mice have
reduced fibrosis in a liver injury model [159].
Care should be taken when interpreting the results
of studies on the DPIV and FAP gko mice because
these mice have dual ablation of enzymatic and extra-
enzymatic activities, and therefore the results may not
accurately reflect the effect of DP inhibitors, which
only inhibit enzymatic functions. The gko mice could
still be useful to prove that the effect of an inhibitor is
DPIV or FAP specific and not caused by the nature of
the compound. In any case, it is essential to carefully
distinguish the enzymatic roles of a DP from its extra-
enzymatic roles in any given cell type. The apparently
normal phenotype of the DPIV gko and FAP gko

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-

tor, PT100 (Val-boro-Pro), slows growth of syngeneic
tumours derived from fibrosarcoma, lymphoma, mela-
noma and mastocytoma cell lines to the same extent in
both wild-type and DPIV gko mice [58], and reduces
myeloma growth and bone disease [160]. In these cases
it is not clear which DP(s), when inhibited, have anti-
tumorigenic effects, or whether inhibiting multiple DPs
has a synergistic effect. Further study using specific
inhibitors is required to understand the mechanisms
involved. It may be that in some cancers DP inhibition
attenuates tumour growth, while extra-enzymatic DP
functions have no effect, or extra-enzymatic and
enzymatic activities are synergistic.
There is some evidence in the literature that DPIV-
and FAP-exerted effects on cell behaviour are cell-type
dependent. For example, while FAP overexpression in
293T cells was associated with decreased cell adhesion
and cell migration, contrasting effects, namely
increased cell adhesion and migration, were found with
the LX-2 human stellate cell line [50]. In other
instances, while anti-tumorigenic effects were associ-
ated with increased DPIV expression in melanocytes,
nonsmall cell lung carcinoma, prostate cancer and neu-
roblastoma cell lines [90–92,95], anti-tumorigenic
effects were conversely associated with decreased DPIV
expression in the Karpas 299 T-anaplastic cell lym-
phoma line [96]. Another comparative study found
that activation of DPIV in hepatic carcinoma cell lines
induces cell apoptosis, but DPIV in Jurkat T cells con-
versely plays a role in cell survival [161]. DPIV expres-

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

and DP9 in the DPIV gko mouse [12]. Yet another
potential advantage is that in certain cell micro-
environments, extra-enzymatic functions could be
anti-tumorigenic, while enzymatic functions may have
pro-tumorigenic properties. Thus, targeting DP enzyme
activity may be useful in certain therapies without
disrupting the beneficial effect of extra-enzymatic
functions.
The crystal structures of DPIV and FAP [3,163],
and the predicted structures of DP8 and DP9
[140,162], at first glance reveal almost identical fold
and general topology amongst the family members.
These proteins are composed of an N-terminal b-pro-
peller domain and a C-terminal a ⁄ b-hydrolase domain.
The a ⁄ b-hydrolase domain, containing the catalytic
triad, is highly conserved throughout this protein fam-
ily. The b-propeller domain, which is associated with
extra-enzymatic functions, is variable. The active site,
buried deep within the protein, is formed by amino
acids from each domain and includes the catalytic
triad and both conserved and variable residues. These
proteins are hollow and accommodate the substrate,
which is stabilized within the active site by these struc-
tures (Fig. 4A).
For development of inhibitors selective for each DP,
it is helpful to carefully consider structural differences,
particularly around the active site. In order to develop
selective inhibitors, current research has therefore
focused on these variable regions and on the diversity
of each DPIV gene family protein (Fig. 4B). Variable

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

red and fluorine in grey. Polar interactions between sitagliptin and
the surrounding structural motifs are denoted by black dotted lines.
Rational drug design for the DPIV gene family proteins focuses on
the variable regions presented by the P2-loop (cyan) and the R-loop
(dark green), and on the acidic pocket presented by the Asp (yellow
sphere) [162]. The image was generated using
PYMOL (DeLano WL:
http: ⁄⁄www.pymol.org).
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 1135
reported [152,153,165], but none can distinguish DP8
from DP9. Comparison of the crystal structures of
FAP and DPIV (52% amino acid identity) reveal one
major difference in the vicinity of the active site.
Ala657 in FAP, instead of Asp663 in DPIV, lessens
the acidity and increases the size of this pocket, mak-
ing FAP capable of endopeptidase activity [3]. Inhibi-
tors for FAP have been developed that utilize these
different characteristics at the active site and are selec-
tive through its predominant endopeptidase activity
versus its DP activity [4].
Concluding remarks
The recent spotlight on the multifunctional DPIV
family as therapeutic targets has highlighted their
interesting biological properties as enzymes in metabo-
lism, cell biology and immunology (Fig. 5) and the
need for further insight into the therapeutic potential
of DP inhibitors in pathogenic conditions, such as can-
cer. To gain a better understanding of the effectiveness
and outcomes of therapeutic DP inhibitors, it will be

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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