Functional interaction between E-cadherin and alphav-containing integrins in carcinoma cells.
We have demonstrated the possibility of cross-talk between E-cadherin and alphav integrins in breast carcinoma cells. Using the function-blocking anti-alphav monoclonal antibody 17E6, applied to monolayer cultures of breast cancer lines, it was found that treatment of cells possessing detergent-insoluble (implying attachment to the actin cytoskeleton) E-cadherin resulted in the adoption of a spheroid configuration of cell growth. This effect was dependent upon not just alphav occupancy but also receptor aggregation. Thus in vitro alphav-dependent adhesion suppresses E-cadherin-mediated morphological changes. To investigate whether manipulation of E-cadherin would, conversely, modulate integrin activity we introduced a dominant-negative E-cadherin construct into one of the lines, ZR75-1, giving rise to the cell line ZR-E2R1. Surface expression of endogenous E-cadherin was downregulated (by around 25%), whereas beta-catenin levels were increased two- to threefold in ZR-E2R1 cells. There was also a highly significant increase in migration of ZR-E2R1 cells (relative to control cells) toward vitronectin (P<0.001), but not toward collagen type I, fibronectin or laminin. Such increased migration could be abrogated totally by antibody blockade of alphavbeta5 and alphavbeta1 integrins. There was no detectable change in alphav integrin levels. These data suggest that the introduction of a dominant-negative E-cadherin mutant into ZR75-1, in addition to a loss of cohesion, generates a signal (or signals) which increases migration towards vitronectin through increased activity of alphav integrins.
von Schlippe
M
M
Richard Dimbleby Department of Cancer Research, Imperial Cancer Research Fund, Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.
Marshall
J F
JF
Perry
P
P
Stone
M
M
Zhu
A J
AJ
Hart
I R
IR
D000199:Actins / Q000032:analysis; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D002465:Cell Movement; D002633:Chemotaxis / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D005260:Female; D005799:Genes, Dominant; D006183:H-2 Antigens / Q000235:genetics; D006801:Humans; D039564:Integrin alphaV; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D019000:Phosphotyrosine / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D012995:Solubility; D018874:Spheroids, Cellular / Q000166:cytology* / Q000378:metabolism; D013347:Subcellular Fractions / Q000737:chemistry; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D019096:Vitronectin / Q000494:pharmacology; D051176:beta Catenin
D000199:Actins; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D003902:Detergents; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D039564:Integrin alphaV; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D019096:Vitronectin; D051176:beta Catenin; D019000:Phosphotyrosine