Model of MT1-MMP and EphA2 interaction in breast carcinoma cells. In invasive cells, where MT1-MMP and EphA2 are coexpressed concomitantly with low ephrinA1, EphA2 promotes Src signaling and further increases MT1-MMP expression. At cell–cell junctions, the few ephrin ligands can be sufficient for limited receptor activation, thus triggering further receptor clustering and activation, which could also involve other ligand-independent mechanisms (Miao and Wang, 2012). Upon MT1-MMP–EphA2 interaction on the cell surface, cleavage of active EphA2 by MT1-MMP triggers Src activity-dependent intracellular translocation of the receptor parallel with increased actomyosin contractility through RhoA activation. These signaling events promote cell–cell repulsion, junctional disassembly, and dissemination of motile single cells within collagen and in vivo. Consistent with the model, prominent intracellular localization of EphA2-D/I can reflect increased cleavages and subsequent internalization events, although intracellular processing of this cleavage-prone receptor also remains a possibility.