Timp‐2 binding with cellular MT1‐MMP stimulates invasion‐promoting MEK/ERK signaling in cancer cells

Abstract

Both invasion‐promoting MT1‐MMP and its physiological inhibitorTIMP‐2 play a significant role in tumorigenesis and are identified in the most aggressive cancers. Despite its antiproteolytic effects in vitro, clinical data suggest that TIMP‐2 expression is positively associated with tumor recurrence, thus emphasizing the wide‐ranging role of TIMP‐2 in malignancies. To shed light on this role of TIMP‐2, we report that low concentrations of TIMP‐2, by interacting with MT1‐MMP (a specific membrane receptor of TIMP‐2), induce the MEK/ERK signaling cascade in fibrosarcoma HT1080 cells which express MT1‐MMP naturally. TIMP‐2 binding with cell surface‐associated MT1‐MMP stimulates phosphorylation of MEK1/2, which is upstream of ERK1/2, and the ERK1/2 substrate p90RSK. Consistent with volumes of literature, we confirmed that the activation of ERK stimulated cell migration. Both the transcriptional silencing of MT1‐MMP and the inhibition of MEK1/2 reversed the signaling effects of TIMP‐2/MT1‐MMP while the active site‐targeting MMP inhibitor GM6001 did not. Our data suggest that both the interactions of TIMP‐2 with MT1‐MMP, which activate the pro‐migratory ERK signaling cascade,and the conventional inhibition of MT1‐MMP's catalytic activity by TIMP‐2, play a role in the invasion‐promoting function of MT1‐MMP. The TIMP‐2‐induced stimulation of ERK signaling in cancer cells explains the direct, as opposed to the inverse, association of TIMP‐2 expression with poor prognosis in cancer.