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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Basement Membrane / metabolism
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Binding Sites / physiology
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Cell Line, Tumor
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Cell Membrane / metabolism*
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Enzyme Inhibitors / pharmacology
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Extracellular Matrix / metabolism*
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Fibrosarcoma / metabolism
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Fibrosarcoma / physiopathology*
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HSP90 Heat-Shock Proteins / antagonists & inhibitors
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HSP90 Heat-Shock Proteins / metabolism*
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Humans
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Matrix Metalloproteinase 2 / metabolism*
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Neoplasm Invasiveness / physiopathology*
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Protein Binding / physiology
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Protein Interaction Mapping
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / metabolism
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Protein Structure, Tertiary / physiology
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Proteomics
Substances
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Enzyme Inhibitors
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HSP90 Heat-Shock Proteins
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Protein Isoforms
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Matrix Metalloproteinase 2