title: A novel extracellular Hsp90 mediated co-receptor function for LRP1 regulates EphA2 dependent glioblastoma cell invasion.
abstract: BACKGROUND
  Extracellular 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-EphA2(S897)). We explored whether eHsp90 may confer invasive properties to GBM via regulation of EphA2 mediated signaling.
  
  
  RESULTS
  We find that eHsp90 signaling is essential for sustaining AKT activation, P-EphA2(S897), 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-EphA2(S897) 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Udhayakumar
authors.initials: U
authors.lastname: Gopal
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Bohonowych
authors.forename: Carla
authors.initials: C
authors.lastname: Lema-Tome
authors.forename: Angen
authors.initials: A
authors.lastname: Liu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.forename: Bingcheng
authors.initials: B
authors.lastname: Wang
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Isaacs
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005909:Glioblastoma / Q000201:enzymology* / Q000473:pathology*; D006038:Glyoxylates / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D036104:Receptor, EphA2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015703:Antigens, CD; D006038:Glyoxylates; D018841:HSP90 Heat-Shock Proteins; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C101912:4-nitrophenylglyoxylic acid; D036104:Receptor, EphA2; D051057:Proto-Oncogene Proteins c-akt