Tài liệu Báo cáo khoa học: The undecided serpin The ins and outs of plasminogen activator inhibitor

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 alpha2 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

‘plasminogen activator’; it is now widely appreciated

for its role in the central nervous system [2,3].

Although it can act on its classical substrate, plasmino￾gen, in this compartment, it also associates with other

targets, and in some cases can even act like a cytokine

to activate microglial cells without engaging its cata￾lytic properties [4]. Similarly, the two plasminogen acti￾vator inhibitors are now known to perform additional

functions. PAI-1 can act as an accessory protein that

modulates the association of the uPA receptor with in￾tegrins. This association, in turn, influences cell migra￾tion independently of the PAI-1 protease inhibitory

activity [5,6].

Keywords

gene regulation; plasminogen activator

inhibitor type 2; protease inhibitor; serpin

Correspondence

R. L. Medcalf, Australian Centre for Blood

Diseases, Monash University, 6th Floor

Burnet Building, 89 Commercial Road,

Prahran, 3181 Victoria, Australia

Fax: +61 39903 0228

Tel: +61 39903 0133

E-mail: [email protected]

(Received 31 March 2005, accepted 13 July

2005)

doi:10.1111/j.1742-4658.2005.04879.x

Plasminogen activator inhibitor type-2 (PAI-2) is a nonconventional serine

protease inhibitor (serpin) with unique and tantalizing properties that is

generally considered to be an authentic and physiological inhibitor of uro￾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