IMMUNOLOGY TODAY

uPA, uPAR, PAL I: key intersection

adhesive and chemstactic h of proteslytic,

ighways?

The molecules. their domains and

IMMUNOLOGY TODAY

Adksml

IMMUNOLOGY TODAY

a” achvate chemotaxis. I” these cells,

Jthrr proteinases might substitute for

IPA once the chemotachc epitope has bee”

?xposed’~.

PAI-I negative regulation PAI-I is a 5pe6fic 5erpIn inhiitor that binds

and inhibits the activity of receptor-bound

UPA. PAI-1 Inhibition alsO &ortens “PA

ha&Life by inducing its internalization and

degradation”, a pmc6z.s requiring hvo m-

ceptors. In addition to UPAR the “imacrc-

globulin receptor tlow-density Iipoprotet”

~LDL)_receptor+&ted pmt& KRP)1 is re-

qukd; this transmenlbrane protein has a

binding site for “PA-PA&l (Ref. 18). The

quaternary uPAR-“PA-PAI-i-LRP complex

is i”temaIiz.ed, uPA-PAI-I is delivered to

the Iysosome, and k uPAR is recyckd

back to the ceu swface at the focal con-

tact~‘~~. This mechanism ‘pexposes free

uPAR at a location in which it cm bind

novel UPA and restart its adhesion and

che”wtaxis CycIe (Fig. 1).

PAI-I binds the N-terminai somat+

medii-Iike domain of VN, which lies dose

to the RGD sequence mediating VN-

integnn interachon Thus, PAI-1 prevents

integrin association to VN and hence ceII

adhesion and rnrgration on this substrate

in rifro. Ti-& process is indepmdent of the

supin activity, since PAI- actrve-site

mutants stilt inhibit cell adhesion and

“ugration on VN (Refs 2;. 22). PAI-1

competes with &AR for bmdmg to VN and

hence also inhibits uPAdependcnt ~11

adhesion and migration. Again, PAI- and

uPAR compete for the same region of

VN (R&s 23, 24). Thus, m addlho” to its

se+” activity, competition with VN tar

inkgrins and uPAR accounts for the anti-

adhesive and anh-mrgratory properties of

PA&I.

A self-regulated cell motogen In addihon to ths dii anti-migratory

activity, PAI- also indirectly ensures the

continuation of an adhesion-migration

cycle by intemaIiziig/degradi”g “PA and

e”swing the recycIiig of free surface “PAR

(Refs 19, 20). The various effects of the

“PAR-“PA-PAi-i system dvpr”d on a com-

plex interplay of intexmoIecuIar associ-

ations and are subjected to fine regulahon

(Fig. 1). Pmteulysis of ECM components

by surface-generated pkl,i”, or ““cover-

ing of the chemotactic uPAR epitope, send

a ‘go’ signal and promote ceII migration.

Free ECM PAI-1, on the other hand, pm-

vides a ‘stop’ signal by inhibiting and inter-

nalizing uPA, prevenhng VN-integri” or

VN-oI’AR n-tteractions and thus cell ad-

hesion and migratmn. The subsequent

recycling of free “PAR to the cell surface

rev- the stop s&d by allomng novel

uPA-uPAR interactions and hence novel

adhesion and migration steps. I” the pm-

cess of migration. chemotaxis represents

the motogenic effect, while binding of

“PAR to VN and integriw represents a

regulated Isubstrate-dependent) ‘pause’

signa for the cell, this beiig a necessary m-

tennediite step in cell migration. In this

way, the surface location of uPAR and thz

signal it Aan send can be continuously

changed through the interplay of “I’/ and

PA&I. WI-& these mechanisms have princi-

paIIy bee” dixovered in culhrred celIs 61

oitro, their relevance in aim is clearly

demonstrated by the immunodefinent phe-

notype of the uPA-‘- mice’.

Conduding remarks

The discovexy that the “PA-“PAR-PAI-

system is involved in immune responses

opens a new field of study. Its relevance m

the response to various types of “nmune

stbn”Ii and possibly 1” tmmunodehciencies

now need to be estabhshed.

The work from the author’s laboratory was ~~ppxted by :he AIRC LAssonarwne ltabana

Rxerche sul Cancm) and the AIDS fund of the

lhban Mmwry of Health, and was camed out

by F Fanoh, B Degryse, M Resnah, N Sidenius

and C Suer The Author 15 espenally f@efuul

:o R Pad, and P Dellabona for many helpful

dlKuss,ons

SEPTEMBER I997