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Functional proteomic screens reveal an essential extracellular role for hsp90α in cancer cell invasiveness

Nature Cell Biology volume 6, pages 507–514 (2004)Cite this article

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 hsp90α isoform, but not hsp90β, is expressed extracellularly where it interacts with the matrix metalloproteinase 2 (MMP2). Inhibition of extracellular hsp90α decreases both MMP2 activity and invasiveness. This role for extracellular hsp90α in MMP2 activation indicates that cell-impermeant anti-hsp90 drugs might decrease invasiveness without the concerns inherent in inhibiting intracellular hsp90.

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Figure 1: Generation of HT-1080 cell surface binders.
Figure 2: FALI screening of HT-1080 cell surface binders.
Figure 3: Hsp90α is an extracellular protein on HT-1080 cells and in conditioned medium.
Figure 4: FALI with anti-hsp90 antibodies and pharmacological agents inhibit invasion.
Figure 5: Hsp90α interacts with and mediates MMP2 activity extracellularly.
Figure 6: Extracellular inhibition of hsp90α decreases invasion and active MMP2 protein.

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Acknowledgements

We thank M. Berne for performing the mass spectrometry analysis on 1.5.1 immunoprecipitates, and J. Dice, J. Kerner and K. Sloan for critical reading of the manuscript. This work was supported in part by grants from the National Cancer Institute (to D.G.J.), a National Institutes of Health Training grant (B.K.E.) and a National Institutes of Health Program grant to the Gastroenterology Research on Absorptive and Secretory Processes group (GRASP).

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  1. Takashi Sakurai

    Present address: RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan

Authors and Affiliations

  1. Department of Physiology, Tufts University School of Medicine, Boston, 02111, MA, USA

    Brenda K. Eustace, Takashi Sakurai, Jean K. Stewart, Dean Yimlamai & Daniel G. Jay

  2. Xerion-Pharmaceuticals AG, Sauerbruchstrasse 50, Munich, D-81377, Germany

    Christine Unger, Carol Zehetmeier, Blanca Lain, Claudia Torella, Stefan W. Henning, Gerald Beste & Leodevico L. Ilag

  3. Cell and Cancer Biology Branch, National Cancer Institute, Rockville, 20850, MD, USA

    Bradley T. Scroggins & Len Neckers

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C.U., C.Z., B. L., C.T., S.W.H., G.B., L.L.I. and D.G.J. received funding (research support and salaries) from Xerion Pharmaceuticals.

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Eustace, B., Sakurai, T., Stewart, J. et al. Functional proteomic screens reveal an essential extracellular role for hsp90α in cancer cell invasiveness. Nat Cell Biol 6, 507–514 (2004). https://doi.org/10.1038/ncb1131

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