THE STRUCTURE AND FUNCTION OF THE UROKINASE RECEPTOR, A MEMBRANE-PROTEIN GOVERNING PLASMINOGEN ACTIVATION ON THE CELL-SURFACE

Proteolytic degradation processes, resulting from the activation of pl asminogen by the specific enzyme, urokinase plasminogen activator (uPA ), take place in the extracellular matrix during cancer invasion as we ll as in tissue remodelling under certain normal-physiological conditi ons, The uPA receptor, uPAR, is a cell-surface protein which plays an important role in the localization and regulation of these processes. In the present article a number of established conclusions concerning the structure and function of uPAR are presented, and in addition vari ous models are discussed which might explain additional observations f or which the mechanisms involved have not yet been clarified experimen tally. uPAR is a highly glycosylated, 3-domain protein, anchored in th e plasma membrane by a glycolipid moiety, The domain organization is i mportant for efficient ligand-binding, and the NH2-terminal domain is directly involved in the molecular contact with uPA. the receptor bind s uPA as well as its proenzyme, pro-uPA, in such a manner that the act ivation cascade can occur directly on the cell surface. Furthermore, t he activation rates are enhanced relative to the situation in solution , probably due to an interplay between uPAR and other, unidentified co mponents, In addition to the function in the regulation of proteolysis , uPAR seems to play a role in internalization processes and in cellul ar signal transduction and adhesion, A few reagents have been identifi ed which are capable to inhibit the interaction between uPAR and uPA. The growing knowledge on the structure and function of uPAR which is a result of protein chemical analyses, functional studies and analyses of other, interacting components, should help to obtain a better under standing of the regulation of extracellular proteolysis, In conjunctio n with the continuous identification of inhibitory reagents, this know ledge should open the possibility to interfere with the resulting, deg radative events.