Epha2 cleavage by MT1-MMP triggers single cancer cell invasion via homotypic cell repulsion

Abstract

Changes in EphA2 signaling can affect cancer cell-cell communication and motility through Ceffects on actomyosin contractility. However, the underlying cell-surface interactions and molecular mech-anisms of how EphA2 mediates these effects have re-mained unclear. We demonstrate here that EphA2 and membrane-anchored membrane type-1 matrix metallo-proteinase (MT1-MMP) were selectively up-regulated and coexpressed in invasive breast carcinoma cells, where, upon physical interaction in same cell-surface complexes, MT1-MMP cleaved EphA2 at its Fibronectin type-III do-main 1. This cleavage, coupled with EphA2-dependent Src activation, triggered intracellular EphA2 translo-cation, as well as an increase in RhoA activity and cell junction disassembly, which suggests an overall repul-sive effect between cells. Consistent with this, cleavage-prone EphA2-D359I mutant shifted breast carcinoma cell invasion from collective to rounded single-cell invasion within collagen and in vivo. Up-regulated MT1-MMP also codistributed with intracellular EphA2 in invasive cells within human breast carcinomas. These results reveal a new proteolytic regulatory mechanism of cell-cell signaling in cancer invasion. © 2013 Sugiyama et al.