title: Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness.
abstract: Tumour cell invasiveness is crucial for cancer metastasis and is not yet understood. Here we describe two functional screens for proteins required for the invasion of fibrosarcoma cells that identified the molecular chaperone heat shock protein 90 (hsp90). The hsp90 alpha isoform, but not hsp90 beta, is expressed extracellularly where it interacts with the matrix metalloproteinase 2 (MMP2). Inhibition of extracellular hsp90 alpha decreases both MMP2 activity and invasiveness. This role for extracellular hsp90 alpha in MMP2 activation indicates that cell-impermeant anti-hsp90 drugs might decrease invasiveness without the concerns inherent in inhibiting intracellular hsp90.
authors.affiliation: Department of Physiology, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Brenda K
authors.initials: BK
authors.lastname: Eustace
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Jean K
authors.initials: JK
authors.lastname: Stewart
authors.forename: Dean
authors.initials: D
authors.lastname: Yimlamai
authors.forename: Christine
authors.initials: C
authors.lastname: Unger
authors.forename: Carol
authors.initials: C
authors.lastname: Zehetmeier
authors.forename: Blanca
authors.initials: B
authors.lastname: Lain
authors.forename: Claudia
authors.initials: C
authors.lastname: Torella
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Henning
authors.forename: Gerald
authors.initials: G
authors.lastname: Beste
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Scroggins
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
authors.forename: Leodevico L
authors.initials: LL
authors.lastname: Ilag
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Jay
mesh_terms: D001485:Basement Membrane / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism*; D005354:Fibrosarcoma / Q000378:metabolism / Q000503:physiopathology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D011485:Protein Binding / Q000502:physiology; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D040901:Proteomics
chemical_list: D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D020033:Protein Isoforms; D020778:Matrix Metalloproteinase 2