title: 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 effects on actomyosin contractility. However, the underlying cell-surface interactions and molecular mechanisms of how EphA2 mediates these effects have remained unclear. We demonstrate here that EphA2 and membrane-anchored membrane type-1 matrix metalloproteinase (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 domain 1. This cleavage, coupled with EphA2-dependent Src activation, triggered intracellular EphA2 translocation, as well as an increase in RhoA activity and cell junction disassembly, which suggests an overall repulsive 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.
authors: Research Programs Unit, Genome-Scale Biology, Haartman Institute, Biomedicum Helsinki, University of Helsinki, FI-00014 Helsinki, Finland.
authors: Nami
authors: N
authors: Sugiyama
authors: Erika
authors: E
authors: Gucciardo
authors: Olga
authors: O
authors: Tatti
authors: Markku
authors: M
authors: Varjosalo
authors: Marko
authors: M
authors: Hyytiäinen
authors: Matthias
authors: M
authors: Gstaiger
authors: Kaisa
authors: K
authors: Lehti
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology / Q000556:secondary*; D045744:Cell Line, Tumor; D048430:Cell Shape; D003094:Collagen / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008207:Lymphatic Metastasis; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D036104:Receptor, EphA2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D059010:Single-Cell Analysis; D059008:Time-Lapse Imaging; D046888:Tissue Array Analysis; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; C066737:RHOA protein, human; D003094:Collagen; D036104:Receptor, EphA2; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D020742:rhoA GTP-Binding Protein
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