MINIREVIEW
The undecided serpin
The ins and outs of plasminogen activator inhibitor type 2
Robert L. Medcalf and Stan J. Stasinopoulos
Australian Centre for Blood Diseases, Monash University, Prahran, Victoria, Australia
Introduction
The plasminogen activating cascade became a much
investigated enzyme system during the early 1980s,
mainly for its role in maintaining vascular patency and
for its effect on the extracellular matrix in the context
of wound healing and cell migration. The controlled
generation of the powerful protease, plasmin, from
its precursor plasminogen seemed to be a relatively
straightforward process at the outset: two serine pro-
teases had been identified that could specifically cleave
plasminogen and produce active plasmin. These pro-
teases (tissue-type- and urokinase-type plasminogen
activator; tPA, uPA) were in turn specifically inhibited
by plasminogen activator inhibitors (PAIs)-types 1 and
2, both of which belong to the serine protease inhibitor
(serpin) superfamily. Other cofactors, such as the ser-
pin alpha
2
antiplasmin, the urokinase receptor (uPAR)
and fibrin, were also shown to play important roles in
regulating plasmin formation and activity [1]. This
may have been the general consensus in the late 1980s,
but nowadays it has become clear that many of the
individual components of the fibrinolytic ⁄ plasminogen
activating system perform other roles that could not
have been foreseen. tPA, for example, is not just a

kinase. However, the fact that only a small percentage of PAI-2 is secreted
has been a long-standing argument for alternative roles for this serpin.
Indeed, PAI-2 has been shown to have a number of intracellular roles: it
can alter gene expression, influence the rate of cell proliferation and differ-
entiation, and inhibit apoptosis in a manner independent of urokinase inhi-
bition. Despite these recent advances in defining the intracellular function
of PAI-2, it still remains one of the most mysterious and enigmatic mem-
bers of the serpin superfamily.
Abbreviations
ARE, AU-rich element; IL, interleukin; K5, keratin 5; LPS, lipopolysaccharide; ov, ovalbumin; PAI, plasminogen activator inhibitor; PAUSE-1,
PAI-2-upstream silencer element-1; Rb, retinoblastoma; serpin, serine protease inhibitor; TNF, tumour necrosis factor; tPA, tissue-type
plasminogen activator; TTP, tristetraprolin; uPA, urokinase-type plasminogen activator; uPAR, urokinase receptor.
4858 FEBS Journal 272 (2005) 4858–4867 ª 2005 FEBS
For PAI-2, there was a strong suspicion soon after
its discovery that the real function of this inhibitor
had been overlooked. From a teleological viewpoint,
a non-uPA inhibitory role was expected, as the
majority of PAI-2 was found in a location where its
intended or perhaps presumed natural target (i.e.
uPA) did not even exist, that being the cell cytosol
[7]. This minireview will focus on the cellular and
molecular biology of PAI-2 and highlight some of
the most recent findings on the role and impressive
pattern of regulation of this enigmatic protease inhi-
bitor. Although new data is emerging, PAI-2 is still
one of the most cryptic protease inhibitors known
and its role in biology and pathophysiology is still
being unravelled.
General biology of PAI-2
PAI-2 was defined as a placental tissue-derived uPA

serine protease inhibitors known as the ovalbumin
(ov)-serpins, with ovalbumin being the prototypical
member of this family [15]. Ovalbumin-serpins share
a common genomic structure and all lack conven-
tional signal sequences and are, for the most part,
located intracellularly. Closer examination of the
genomic structure of PAI-2 revealed another distinctive
feature, that being an extension of exon 3 that encoded
a unique domain bridging helices C and D of the pro-
tein. This so-called C-D interhelical domain [16], other-
wise known as the C-D loop, has since been implicated
in the function of PAI-2. Glutamine residues in the
C-D loop can be crosslinked by tissue transglutaminase
and factor XIII to structures in trophoblasts and to
fibrin [16–18]. Moreover, the C-D loop has been
shown to bind noncovalently to annexins, retinoblastoma
protein and a number of unidentified proteins [19,20].
Using the expressed C-D interhelical loop as bait, Fan
et al. identified the b1 subunit of the proteosome as
a binding partner [21]. The physiological relevance
of these findings remains to be clarified, but none-
theless points to diverse roles of the C-D loop in
PAI-2 function.
Polymerization of PAI-2
Many serpins have been shown to undergo loop sheet
polymerization. Generally, polymerization occurs due
to a genetic aberration, which results in serious patho-
logical consequences due to conformational changes of
these proteins [22]. PAI-2 is also able to polymerize,
but in contrast to the other polymerizing serpins this is

placenta [26]. Lower constitutive levels of PAI-2 are
also found in other cells, including cells of neuronal
origin [27]. Plasma levels of PAI-2 are usually low or
undetectable; however, they rise significantly in some
forms of monocytic leukaemia [28]. One of the most
physiologically striking observations for PAI-2 con-
cerns its association with pregnancy. Plasma levels of
PAI-2 increase impressively during the third trimester
of pregnancy (up to 250 ngÆmL
)1
) and are maintained
at these levels for up to 1 week postpartum and then
rapidly decline [10]. The tissue source of plasma PAI-2
is the placenta itself. Indeed, PAI-2 is highly expressed
in trophoblasts [29,30] and it was conjectured that
PAI-2 acted to protect the placenta from proteolytic
degradation towards the end of the gestational period
and to regulate postpartum haemostasis. However, a
placental associated PAI-2 sensitive protease is yet to
be described. Perhaps the role of PAI-2 in the placenta
is unrelated to protease inhibition. In this regard, it is
interesting to point out that PAI-2 forms complexes
with other placental proteins, including vitronectin
[9,31], but the functional significance of this in terms
of placental biology is unknown.
The association of PAI-2 with pregnancy and its
placenta-specific expression suggested that PAI-2
might perform a critical function during foetal devel-
opment. If this were indeed the case, one would have
predicted a developmental abnormality in PAI-2

[35] implying that PAI-2 itself is a substrate for a pro-
tease in these cells.
To determine the consequences of dysregulation of
PAI-2 on epidermal differentiation, Zhou et al. [36]
produced transgenic mice that overexpressed PAI-2 in
the proliferating layers of mouse epidermis and hair
follicle cells by placing the PAI-2 transgene under the
control of the keratin 5 (K5) promoter. Although the
presence of PAI-2 had no effect on skin morphology
or proliferation under normal conditions, the PAI-2
overexpressing mice were found to be highly suscept-
ible to chemically induced papilloma formation. The
means by which PAI-2 promoted papilloma formation
is unknown, but may have been related to its reported
antiapoptotic effect (see below) since cessation of
tumour promoting treatment in control mice resulted
in extensive apoptosis of the papilloma but not in the
K5-PAI-2 transgenic mouse.
Leukocyte biology
Monocytes and macrophages express PAI-2 and levels
are impressively increased in these cells following sti-
mulation with tumour necrosis factor (TNF) [14] and
lipopolysaccharide (LPS) [37,38]. Induction of PAI-2
gene expression has been associated with monocyte dif-
ferentiation, at least in the U-937 monocyte-like cell
system [39], suggesting a role for PAI-2 in this process.
In the mouse system PAI-2 does not appear to be
indispensable for leukocyte development as PAI-2
– ⁄ –
mice exhibit normal leukocyte recruitment and appear

P1 position (Arg380). The presence of wild type PAI-2
caused a significant decrease in THP-1 cell prolifer-
ation, reduction in DNA synthesis and a phenotypic
change following phorbol ester-induced differentiation.
The ability of PAI-2 to alter the differentiation process
was dependent on its active form as cells expressing
PAI-2
Ala380
did not display these changes. This study
demonstrated for the first time an intracellular role for
active PAI-2 in monocytes. These results were con-
sistent with the possibility that PAI-2 disrupted an
intracellular protease(s) that was involved in cell prolif-
eration and ⁄ or differentiation although no such target
protease has been detected thus far.
PAI-2 is also present at very high levels in eosino-
philic leukocytes. Indeed the level of PAI-2 in these
cells was shown to be the highest among all other leu-
kocyte subtypes [44]. Furthermore, PAI-2 was localized
to eosinophil-specific granules and shown to be still
capable of inhibiting urokinase. It was suggested that
PAI-2 might play a role in eosinophil mediated inflam-
mation and tissue remodelling.
Role of intranuclear PAI-2
A number of Ov-serpins have been detected within the
nuclear compartment, including bomapin, PI-9, and
maspin [45–47]. PAI-2 has also been shown to have a
nuclear presence [20,45,46] yet the physiological role of
PAI-2 in this compartment is unknown. However, in
a study by Darnell et al. nuclear-located PAI-2 was

Overexpression of PAI-2 in melanoma cells prevented
spontaneous metastasis of transplanted cells in scid
mice [54], while overexpression of PAI-2 in HT-1080
cells has also been shown to reduce uPA-dependent
cell movement in vitro and metastatic development
in vivo [55]. The ability of PAI-2 to selectively bind to
cell surface bound uPA (via uPAR) and subsequently
be internalized [56] has prompted studies to assess the
effectiveness of PAI-2 as a delivery vehicle for isotopes
(
213
Bi) and toxins that can be targeted to uPA-bearing
cancer cells This approach has provided positive out-
comes at least in some preclinical studies [57–59].
Apoptosis
Circumstantial evidence that first implicated PAI-2 as
an inhibitor of apoptosis came from genetic associ-
ation studies with BCL-2 [60]. The BCL-2 proto-
oncogene was discovered over 15 years ago as the
archetype inhibitor of apoptosis. Evidence that BCL-2
was playing such a role in humans came from studies
in patients with follicular lymphoma. In these patients,
a translocation event occurs between chromosomes 14
and 18 t(14; 18) that brings the BCL-2 gene into juxta-
position with the locus of the immunoglobulin heavy
chain, resulting in overexpression of BCL-2 [61]. This
in turn inhibits the apoptotic process of the lym-
phoma. The relevance of this to PAI-2 stemmed from
the fact that the PAI-2 gene is located less than
300 mbp from the BCL-2 gene and is translocated

the expression of a battery of antiviral genes [65].
Shafren et al. [66] also demonstrated the same PAI-2
over-expressing HeLa cells were protected from lytic
infection by human picornaviruses. In this case, PAI-2
promoted the transcriptional down-regulation of sur-
face expression of picornavirus receptors (decay accel-
erating factor, intercellular adhesion molecule-1 and
coxsachievirus-adenovirus receptor; DAF, ICAM-1
and CAR, respectively). These observations further
support the growing body of evidence [42,43] that
intracellular expression of PAI-2 is linked to a signal-
ling pathway(s) that can reprogram gene expression.
One may even speculate that PAI-2 could play a role
in the innate immune response since its expression is
commonly associated with inflammation and the host
response to infection.
PAI-2 gene expression and regulation
Based on data accumulated over the past 17 years, it is
evident that the PAI-2 gene expression can be induced
by a wide range of agonists. Moreover the level of
PAI-2 gene induction in some examples is quite extra-
ordinary. Agonists of PAI-2 induction include growth
factors (transforming growth factor-b, epidermal
growth factor and monocyte-colony stimulating fac-
tor; TGFb, EGF and M-CSF, respectively), hormones
(retinoic acid, dexamethasone and vitamin D3), cyto-
kines [TNFa, interleukin (IL)-1 and IL-2)], vasoactive
peptides (angiotensin II), toxins (dioxin and endotoxin)
and tumour promoters (phorbol esters and okadaic
acid) [26,67]. PAI-2 mRNA expression is also strongly

increases in the rate of PAI-2 transcription [39]. Similar
studies in HT-1080 fibrosarcoma cells demonstrated a
transcriptional component following TNF-mediated
induction of PAI-2 expression [14]. These studies led to
an analysis of the PAI-2 promoter [77,78]. DNase-1
protection experiments indicated that the proximal
region of the PAI-2 promoter possessed a congested
arrangement of cis-acting elements. Of these, only the
AP1-like elements, AP1a (TGAATCA, )103 to )97)
and AP1b (TGAGTAA, )114 to )108), and a cAMP
responsive element (CRE)-like element (TGACCTCA,
)187 to )182) [77,79] were shown to have functional
activity during transcriptional regulation. Curiously, a
repressor element located between )219 and )1100 was
suggested to play a role during TNF induction [80].
The identification of the exact sequence within this
The undecided serpin R. L. Medcalf and S. J. Stasinopoulos
4862 FEBS Journal 272 (2005) 4858–4867 ª 2005 FEBS
region and trans-acting factors responsible for this
activity have not been reported. Antalis et al. [81]
characterized 5.1 kb of 5¢ flanking region in U937 cells
by deletion analysis and found a silencer between
)1977 and )1675 that acts in an orientation- and
position-independent but not cell-specific manner. The
silencer activity was localized to a 28 bp sequence
containing a 12 bp palindrome at position )1832,
CTCTCTAGAGAG, which was termed PAI-2-
upstream silencer element-1 (PAUSE-1). Later analysis
defined the minimal functional PAUSE-1 element as
TCTN

most notably at the level of mRNA instability.
PAI-2 mRNA contains a functional nonameric
(UUAUUUAUU) AU-rich element (ARE) in its 3¢-un-
translated region [85]. Mutagenesis of this element par-
tially stabilized the normally unstable PAI-2 mRNA,
hence revealing a functional role for this motif [85,86].
This element also provides binding sites for several
ARE binding proteins, including the stabilizing protein
HuR [86] and the mRNA destabilizing protein tristetr-
aprolin (TTP) [87]. HuR is a member of the Hu family
of mRNA binding proteins and has been associated
with promotion of mRNA stability [88]. TTP, on the
other hand, is a potent mRNA destabilizing protein
that associates with ARE elements in cytokine tran-
scripts, including TNF a [89] and IL-3 [90]. Overexpres-
sion of TTP in HEK 293 cells transfected with a
constitutively active PAI-2 expression vector resulted
in loss of PAI-2 mRNA, suggesting that TTP can
indeed regulate PAI-2 expression [86]. Other cytoplas-
mic and nuclear proteins also bind to the ARE with
the PAI-2 3¢-UTR [85,86] but these are yet to be iden-
tified. The PAI-2 transcript also possesses another
instability determinant located within exon 4 of the
PAI-2 coding region [91]. UV-crosslinking studies have
identified two RNA-binding proteins (approximately
50–52 kDa) that specifically interact with this
sequence. Taken together, the data published to date
suggest that PAI-2 mRNA stability is influenced by
elements located within both the coding region and the
3¢-UTR. It remains to be determined whether these

momentum but more direct and physiologically
focused experiments are needed in order to define its
undisputed intracellular function. It is anticipated that
this information will be forthcoming through a more
extensive analysis of the PAI-2
– ⁄ –
mice. Results from
these experiments are eagerly awaited.
Acknowledgements
This study was supported by grants obtained by RLM
from the National Health and Medical Research
Council of Australia.
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