Functional proteomic screens reveal an essential extracellular role for hsp90 in cancer cell invasiveness
Brenda K. Eustace1, Takashi Sakurai1, 2, Jean K. Stewart1, Dean Yimlamai1, Christine Unger3, Carol Zehetmeier3, Blanca Lain3, Claudia Torella3, Stefan W. Henning3, Gerald Beste3, Bradley T. Scroggins4, Len Neckers4, Leodevico L. Ilag3 & Daniel G. Jay1
1 Department of Physiology, Tufts University School of Medicine, Boston, MA 02111, USA.
2 Present address: RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
3 Xerion-Pharmaceuticals AG, Sauerbruchstrasse 50, D-81377, Munich, Germany.
4 Cell and Cancer Biology Branch, National Cancer Institute, Rockville, MD 20850, USA.
Correspondence should be addressed to Daniel G. Jay daniel.jay@tufts.edu
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 isoform, but not hsp90, is expressed extracellularly where it interacts with the matrix metalloproteinase 2 (MMP2). Inhibition of extracellular hsp90 decreases both MMP2 activity and invasiveness. This role for extracellular hsp90 in MMP2 activation indicates that cell-impermeant anti-hsp90 drugs might decrease invasiveness without the concerns inherent in inhibiting intracellular hsp90.
Nature Cell Biology 6, 507 - 514 (2004)
Published online: 16 May 2004; | doi:10.1038/ncb1131
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