EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt.
Both pro- and antioncogenic properties have been attributed to EphA2 kinase. We report that a possible cause for this apparent paradox is diametrically opposite roles of EphA2 in regulating cell migration and invasion. While activation of EphA2 with its ligand ephrin-A1 inhibited chemotactic migration of glioma and prostate cancer cells, EphA2 overexpression promoted migration in a ligand-independent manner. Surprisingly, the latter effects required phosphorylation of EphA2 on serine 897 by Akt, and S897A mutation abolished ligand-independent promotion of cell motility. Ephrin-A1 stimulation of EphA2 negated Akt activation by growth factors and caused EphA2 dephosphorylation on S897. In human astrocytoma, S897 phosphorylation was correlated with tumor grades and Akt activation, suggesting that the Akt-EphA2 crosstalk may contribute to brain tumor progression.
Miao
Hui
H
Department of Medicine, Rammelkamp Center for Research, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. hxm35@case.edu
Li
Da-Qiang
DQ
Mukherjee
Amitava
A
Guo
Hong
H
Petty
Aaron
A
Cutter
Jennifer
J
Basilion
James P
JP
Sedor
John
J
Wu
Jiong
J
Danielpour
David
D
Sloan
Andrew E
AE
Cohen
Mark L
ML
Wang
Bingcheng
B
D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D018450:Disease Progression; D004789:Enzyme Activation; D006801:Humans; D008024:Ligands; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D036082:Receptor, EphA1 / Q000378:metabolism; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism*
D008024:Ligands; D010768:Phosphoserine; D036082:Receptor, EphA1; D036104:Receptor, EphA2; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human