Molecular and functional crosstalk between extracellular Hsp90 and ephrin A1 signaling.

ABSTRACT: The Eph receptor tyrosine kinase family member EphA2 plays a pivotal role in modulating cytoskeletal dynamics to control cancer cell motility and invasion. EphA2 is frequently upregulated in diverse solid tumors and has emerged as a viable druggable target. We previously reported that extracellular Hsp90 (eHsp90), a known pro-motility and invasive factor, collaborates with EphA2 to regulate tumor invasion in the absence of its cognate ephrin ligand. Here, we aimed to further define the molecular and functional relationship between EphA2 and eHsp90. Ligand dependent ephrin A1 signaling promotes RhoA activation and altered cell morphology to favor transient cell rounding, retraction, and diminished adhesion. Exposure of EphA2-expressing cancer cells to ligand herein revealed a unique role for eHsp90 as an effector of cytoskeletal remodeling. Notably, blockade of eHsp90 via either neutralizing antibodies or administration of cell-impermeable Hsp90-targeted small molecules significantly attenuated ligand dependent cell rounding in diverse tumor types. Although eHsp90 blockade did not appear to influence receptor internalization, downstream signaling events were augmented. In particular, eHsp90 activated a Src-RhoA axis to enhance ligand dependent cell rounding, retraction, and ECM detachment. Moreover, eHsp90 signaling via this axis stimulated activation of the myosin pathway, culminating in formation of an EphA2-myosin complex. Inhibition of either eHsp90 or Src was sufficient to impair ephrin A1 mediated Rho activation, activation of myosin intermediates, and EphA2-myosin complex formation. Collectively, our data support a paradigm whereby eHsp90 and EphA2 exhibit molecular crosstalk and functional cooperation within a ligand dependent context to orchestrate cytoskeletal events controlling cell morphology and attachment.

SUBMITTER: Daoud A 

PROVIDER: S-EPMC5739775 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature