Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness.
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.
Eustace
Brenda K
BK
Department of Physiology, Tufts University School of Medicine, Boston, MA 02111, USA.
Sakurai
Takashi
T
Stewart
Jean K
JK
Yimlamai
Dean
D
Unger
Christine
C
Zehetmeier
Carol
C
Lain
Blanca
B
Torella
Claudia
C
Henning
Stefan W
SW
Beste
Gerald
G
Scroggins
Bradley T
BT
Neckers
Len
L
Ilag
Leodevico L
LL
Jay
Daniel G
DG
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
D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D020033:Protein Isoforms; D020778:Matrix Metalloproteinase 2