Activation of the EGFR gene target EphA2 inhibits epidermal growth factor-induced cancer cell motility.
EphA2 overexpression has been reported in many cancers and is believed to play an important role in tumor metastasis and angiogenesis. We show that the activated epidermal growth factor receptor (EGFR) and the cancer-specific constitutively active EGFR type III deletion mutant (EGFRvIII) induce the expression of EphA2 in mammalian cell lines, including the human cancer cell lines A431 and HN5. The regulation is partially dependent on downstream activation of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase and is a direct effect on the EphA2 promoter. Furthermore, EGFR and EphA2 both localize to the plasma membrane and EphA2 coimmunoprecipitates with activated EGFR and EGFRvIII. Ligand activation of EphA2 and EphA2 knockdown by small interfering RNA inhibit EGF-induced cell motility of EGFR-overexpressing human cancer cells, indicating a functional role of EphA2 in EGFR-expressing cancer cells.
Larsen
Alice Bjerregaard
AB
Department of Radiation Biology, Section 6321, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Pedersen
Mikkel Wandahl
MW
Stockhausen
Marie-Thérése
MT
Grandal
Michael Vibo
MV
van Deurs
Bo
B
Poulsen
Hans Skovgaard
HS
D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D066246:ErbB Receptors / Q000819:agonists / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D036104:Receptor, EphA2 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C410723:epidermal growth factor receptor VIII; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D036104:Receptor, EphA2; D020930:MAP Kinase Kinase Kinases