A Novel Extracellular Hsp90 Mediated Co-Receptor Function for LRP1 Regulates EphA2 Dependent Glioblastoma Cell Invasion

Abstract

BackgroundExtracellular Hsp90 protein (eHsp90) potentiates cancer cell motility and invasion through a poorly understood mechanism involving ligand mediated function with its cognate receptor LRP1. Glioblastoma multiforme (GBM) represents one of the most aggressive and lethal brain cancers. The receptor tyrosine kinase EphA2 is overexpressed in the majority of GBM specimens and is a critical mediator of GBM invasiveness through its AKT dependent activation of EphA2 at S897 (P-EphA2S897). We explored whether eHsp90 may confer invasive properties to GBM via regulation of EphA2 mediated signaling.Principal FindingsWe find that eHsp90 signaling is essential for sustaining AKT activation, P-EphA2S897, lamellipodia formation, and concomitant GBM cell motility and invasion. Furthermore, eHsp90 promotes the recruitment of LRP1 to EphA2 in an AKT dependent manner. A finding supported by biochemical methodology and the dual expression of LRP1 and P-EphA2S897 in primary and recurrent GBM tumor specimens. Moreover, hypoxia mediated facilitation of GBM motility and invasion is dependent upon eHsp90-LRP1 signaling. Hypoxia dramatically elevated surface expression of both eHsp90 and LRP1, concomitant with eHsp90 dependent activation of src, AKT, and EphA2.SignificanceWe herein demonstrate a novel crosstalk mechanism involving eHsp90-LRP1 dependent regulation of EphA2 function. We highlight a dual role for eHsp90 in transducing signaling via LRP1, and in facilitating LRP1 co-receptor function for EphA2. Taken together, our results demonstrate activation of the eHsp90-LRP1 signaling axis as an obligate step in the initiation and maintenance of AKT signaling and EphA2 activation, thereby implicating this pathway as an integral component contributing to the aggressive nature of GBM.

Extracellular Heat Shock Protein 90 Signals through Subdomain II and the NPVY Motif of LRP-1 Receptor to Akt1 and Akt2: a Circuit Essential for Promoting Skin Cell Migration In Vitro and Wound Healing In Vivo

“…During skin wound healing, eHsp90␣ drives migration of keratinocytes, dermal fibroblasts, and endothelial cells into the wound bed to promote wound closure (9,10). In tumor progression, eHsp90␣ adds invasion and metastasis of the tumor cells (7,16,18,27,28). However, despite the understanding of eHsp90␣ function in both physiological and pathological processes, the mechanism by which eHsp90␣ promotes cell migration remained elusive.…”

Danger signalling during cancer cell death: origins, plasticity and regulation

“…Ecto-CRT docks on lipid rafts and LRP1 in an inducer-dependent fashion, 7 whereas HSP90 binds to LRP1. 36 To date nothing is known about HSP70's docking patterns, although its relatively homogenous surface distribution as patches and small clumps, 22 which differs from the unevenly distributed patches observed for ecto-CRT, 7,22,37 suggests a different docking entity. In a functional sense, these chaperones have been reported to bind to various receptors on immune cells, like CD91 and certain scavenger receptors.…”

Immunogenic cell death

“…On the surface of the stressed/dying cancer cells, ecto-CRT has been reported to dock on either lipid rafts or LRP1 in an inducer/context-dependent fashion (Gardai et al, 2005, Garg et al, 2012c, whereas HSP90 tends to bind to LRP1 (Gopal et al, 2011). However, to date not much is known about HSP70's docking preferences; interestingly, though HSP70's relatively consistent surface distribution as patches and/or small clumps suggests that it may not share a docking-entity with ecto-CRT since the latter tends to have a more uneven distribution (Gardai et al, 2005, Garg et al, 2012b, Garg et al, 2012c.…”