Dual function of focal adhesion kinase in regulating integrin-induced MMP-2 and MMP-9 release by human T lymphoid cells.

Integrin engagement induces matrix metalloproteinase (MMP) production by lymphocytes, allowing their progression into tissues. Focal adhesion kinase (FAK) is a key component of integrin-mediated signaling pathways regulating cell migration. We explored the role of FAK in integrin-induced gelatinase production by Jurkat T cells. Elevation of FAK expression by transient transfection increased cell invasiveness and gelatinase production and release driven by fibronectin. FAK point mutants revealed that gelatinase release was not dependent on FAK kinase activity but did require Y397, a binding site for Src-type tyrosine kinases. Requirement of Src kinases was further demonstrated by transfection with Src kinase-deficient mutants and treatment with a Src inhibitor. Transfection of truncated forms demonstrated dual functional elements in the FAK molecule. The FRNK fragment decreased gelatinase release, whereas the FAT subfragment enhanced it. FRNK inhibitory signals were transduced through Src-dependent pCAS phosphorylation and subsequent ERK1/2 activation. In contrast, FAT stimulated gelatinase secretion, which was also dependent on Src-kinase activity, was associated with a decreased ERK1/2 phosphorylation. This dual function of FAK in gelatinase secretion is then associated with changes in ERK1/2 activation status, a pathway coordinating cycles of adhesion/release required for cell migration and defines a novel regulatory step in the complex control of MMP function.