Cell adhesion and EGFR activation regulate EphA2 expression in cancer.
EphA2 is frequently overexpressed in cancer, and increasing amounts of evidence show that EphA2 contributes to multiple aspects of the malignant character including angiogenesis and metastasis. Several aspects of the regulation and functional significance of EphA2 expression in cancer are still largely unknown. Here we show that the expression of EphA2 in in vitro cultured cells, is restricted to cells growing adherently and that adhesion-induced EphA2 expression is dependent upon activation of the epidermal growth factor receptor (EGFR), mitogen activated protein kinase kinase (MEK) and Src family kinases (SRC). Moreover, the results show that adhesion-induced EGFR activation and EphA2 expression is affected by interactions with extracellular matrix (ECM) proteins working as integrin ligands. Stimulation with the EphA2 ligand, ephrinA1 inhibited ERK phosphorylation and cancer cell viability. These effects were however abolished by activation of the EGF-receptor ligand system favoring Ras/MAPK signaling and cell proliferation. Based on our results, we propose a regulatory mechanism where cell adhesion induces EGFR kinase activation and EphA2 expression; and where the effect of ephrinA1 mediated reduction in cell viability by inhibiting EphA2 expression is overruled by activated EGFR in human cancer cells.
Larsen
Alice Bjerregaard
AB
Department of Radiation Biology, Copenhagen University Hospital, Denmark.
Stockhausen
Marie-Thérése
MT
Poulsen
Hans Skovgaard
HS
D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002470:Cell Survival; D036382:Ephrin-A1 / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D036104:Receptor, EphA2 / Q000235:genetics* / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D036382:Ephrin-A1; D066246:ErbB Receptors; D036104:Receptor, EphA2; D019061:src-Family Kinases; D020929:Mitogen-Activated Protein Kinase Kinases