Interaction of cells with the extracellular matrix (ECM) plays an important role in the regulation of cell behavior. Formation of adhesive contacts leads to transduction of signals into the cell and results in altered gene expression and modulation of the cellular phenotype. Specific adhesive interactions of the
fibronectin and
vitronectin receptors with their
ligands in the matrix modulates expression of ECM-degrading
metalloproteases. These
proteases are involved in the acquisition of the invasive phenotype by a number of cell types. The activity of matrix
metalloproteases (
MMPs) is reduced by endogenous inhibitors referred to as tissue inhibitors of
metalloproteases (TIMPs). Alterations in the balance between the activity of
MMPs and TIMPs alters cellular invasion through effects on matrix degradation. In this study we demonstrate that inhibition of endogenous
gelatinase A activity in A2058 human
melanoma cells results in enhanced cellular adhesion. To further explore this phenomenon, we have used retroviral
infection vectors to control the amount of the
MMP inhibitor TIMP-2 in human
melanoma A2058 cells. Altering the production of
TIMP-2 modulates not only proteolysis of the extracellular matrix, but also the adhesive and spreading properties of the cells and results in altered cell morphology. These effects of
TIMP-2 appear to be mediated by inhibition of
gelatinase A activity. We conclude that
gelatinase A, in addition to contributing to proteolysis of ECM components, also functions to proteolyse cell surface components that mediate attachment of A2058 cells to the ECM. Thus,
gelatinase A may function to modulate cell attachment and facilitate cell migration and invasion.