Plasminogen activator inhibitor type 2: an intracellular keratinocyte differentiation product that is incorporated into the cornified envelope

Human epidermal keratinocytes synthesize a complex plasminogen activator proteolytic cascade, consisting of two plasminogen activating enzymes and two inhibitors, that is thought to play a role in epidermal migration and differentiation as well as in several cutaneous diseases. Quantification of the plasminogen activator cascade proteins in keratinocytes reveals that plasminogen activator inhibitor type 2 (PAI-2) is distinct from the other components (i.e., urokinase and tissue-type plasminogen activators and inhibitor type 1) in several respects: (i) PAI-2 remains mostly cell-associated, rather than secreted; (ii) The level of cell-associated PAI-2 is at least 50-fold greater than that of the other components; (iii) PAI-2 is the only component whose level is enhanced upon elevation of the Ca2+ concentration, which is well known to induce a more differentiated phenotype in keratinocyte culture. Immunocytochemical localization experiments reveal that most keratinocytes contain PAI-2, which in a subpopulation of more differentiated cells is resistant to detergent extraction. Additional immunocytochemical localization and immunoblot experiments demonstrate that some of the PAI-2 becomes incorporated into the cornified envelope during terminal differentiation of the keratinocyte. These studies raise the possibility that PAI-2 may have an intracellular role associated with the terminal stage of keratinocyte differentiation.