Matrix-dependent proteolysis of surface transglutaminase by membrane-type metalloproteinase regulates cancer cell adhesion and locomotion

Cell invasion requires cooperation between adhesion receptors and matrix me talloproteinases (MMPs). Membrane type (MT)-MMPs have been thought to be pr imarily involved in the breakdown of the extracellular matrix. Our report p resents evidence that MT-MMPs in addition to the breakdown of the extracell ular matrix may be engaged in proteolysis of adhesion receptors on tumor ce ll surfaces. Overexpression of MT1-MMP by glioma and fibrosarcoma cells led to proteolytic degradation of cell surface tissue transglutaminase (tTG) a t the leading edge of motile cancer cells. In agreement, structurally relat ed MT1-MMP, MT2-MMP, and MT3-MMP but not evolutionary distant MT4-MMP effic iently degraded purified tTG in vitro, Because cell surface tTG; represents a ubiquitously expressed, potent integrin-binding adhesion coreceptor invo lved in the binding of cells to fibronectin (Fn), the proteolytic degradati on of tTG by MT1-MMP specifically suppressed cell adhesion and migration on Fn, Reciprocally, Fn in vitro and in cultured cells protected its surface receptor, tTG, from proteolysis by MT1-MMP, thereby supporting cell adhesio n and locomotion. In contrast, the proteolytic degradation of tTG stimulate d migration of cells on collagen matrices. Together, our observations sugge st both an important coreceptor role for cell surface tTG and a novel regul atory function of membrane-anchored MMPs in cancer cell adhesion and locomo tion. Proteolysis of adhesion proteins colocalized with MT-MMPs at discrete regions on the surface of migrating tumor cells might be controlled by com position of the surrounding ECM.