GELATINASE-A ACTIVITY DIRECTLY MODULATES MELANOMA CELL-ADHESION AND SPREADING

Interaction of cells with the extracellular matrix (ECM) plays an impo rtant role in the regulation of cell behavior. Formation of adhesive c ontacts leads to transduction of signals into the cell and results in altered gene expression and modulation of the cellular phenotype. Spec ific adhesive interactions of the fibronectin and vitronectin receptor s with their ligands in the matrix modulates expression of ECM-degradi ng metalloproteases. These proteases are involved in the acquisition o f the invasive phenotype by a number of cell types. The activity of ma trix metalloproteases (MMPs) is reduced by endogenous inhibitors refer red to as tissue inhibitors of metalloproteases (TIMPs). Alterations i n the balance between the activity of MMPs and TIMPs alters cellular i nvasion through effects on matrix degradation. In this study we demons trate that inhibition of endogenous gelatinase A activity in A2058 hum an melanoma cells results in enhanced cellular adhesion. To further ex plore this phenomenon, we have used retroviral infection vectors to co ntrol the amount of the MMP inhibitor TIMP-2 in human melanoma A2058 c ells. Altering the production of TIMP-2 modulates not only proteolysis of the extracellular matrix, but also the adhesive and spreading prop erties of the cells and results in altered cell morphology. These effe cts of TIMP-2 appear to be mediated by inhibition of gelatinase A acti vity. We conclude that gelatinase A, in addition to contributing to pr oteolysis of ECM components, also functions to proteolyse cell surface components that mediate attachment of A2058 cells to the ECM. Thus, g elatinase A may function to modulate cell attachment and facilitate ce ll migration and invasion.