A subset of
Eph receptors and their corresponding
ligands are commonly expressed in
tumor cells where they mediate biological processes such as cell migration and adhesion, whereas their expression in endothelial cells promotes angiogenesis. In particular, the
tumor-specific up-regulation of EphA2 confers properties of increased cellular motility, invasiveness,
tumor angiogenesis, and
tumor progression, and its overexpression correlates with poor prognosis in several
cancer types. The cellular chaperone Hsp90 also plays a significant role in regulating cell migration and angiogenesis, although the full repertoire of motility driving
proteins dependent on Hsp90 function remain poorly defined. We explored the hypothesis that Hsp90 may regulate the activity of EphA2 and examined the potential relationship between
EphA2 receptor signaling and chaperone function. We show that
geldanamycin, an Hsp90 antagonist, dramatically destabilizes newly synthesized
EphA2 protein and diminishes receptor levels in a
proteasome-dependent pathway. In addition,
geldanamycin treatment impairs EphA2 signaling, as evidenced by a decrease in
ligand-dependent receptor phosphorylation and subsequent cell rounding. Therefore, Hsp90 exerts a dual role in regulating the stability of nascent
EphA2 protein and maintaining the signaling capacity of the mature receptor. Our findings also suggest that the
geldanamycin-dependent mitigation of EphA2 signaling in receptor-overexpressing
cancer cells may be sufficient to recapitulate the antimotility effects of this
drug. Finally, the identification of a pharmacologic approach to suppress EphA2 expression and signaling highlights the attractive possibility that Hsp90 inhibitors may have clinical utility in antagonizing EphA2-dependent tumorigenic progression.