Extracellular HSP90: conquering the cell surface.

Abstract

Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone, assisting intracellularly in the folding and conformational regulation of a multitude of client proteins that play a crucial role in growth, cell survival and developmental processes. Moreover HSP90 interacts with a great number of molecules that are involved in the development and/or survival of cancer cells, allowing mutant proteins to retain or gain function while permitting cancer cells to tolerate the imbalanced signaling that such oncoproteins create. Prime examples include the HER-2 receptor, c-Raf-1, Akt/PKB, CDK4 and mutant p53. Highly specific inhibitors of HSP90 have been identified and are currently under clinical evaluation. These include geldanamycin and its derivatives 17-allylamino-17-demethoxygeldanamycin and 17-dimethylaminoethylamino-17-demethoxygeldanamycin, which inhibit cancer cell proliferation in vitro and tumor growth in vivo. Recently, a pool of HSP90 has been identified at the cell surface, where it was shown to be involved in cancer cell invasion. Here, we propose a model concerning the molecular mechanism underlying the role of HSP90 in cancer cell invasion. We suggest that surface HSP90 interacts specifically with the extracellular domain of HER-2 and that this interaction is necessary for the receptor's activation and heterodimerization with ErbB-3, which in turn will mediate signal transduction pathways via MAPK and PI3K-Akt, leading to actin re-arrangement and cell motility. Furthermore we propose that the selective inhibition of cell surface HSP90 with a cell-impermeable function blocking monoclonal antibody, mAb 4C5, may have clinical benefits in limiting cancer invasion and metastasis.

• Authors: Katerina Sidera, Evangelia Patsavoudi
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 7 Issue 11 Pg. 1564-8 (Jun 01 2008) ISSN: 1551-4005 [Electronic] United States
• PMID: 18469526 (Publication Type: Journal Article)

Chemical References

• 4C5 monoclonal antibody
• Antibodies, Monoclonal
• HSP90 Heat-Shock Proteins
• ERBB2 protein, human
• Receptor, ErbB-2
• Receptor, ErbB-3

Topics

• Antibodies, Monoclonal (pharmacology)
• Cell Movement (physiology)
• Dimerization
• Extracellular Matrix (metabolism)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Models, Biological
• Neoplasm Invasiveness (physiopathology)
• Receptor, ErbB-2 (metabolism)
• Receptor, ErbB-3