Extracellular HSP90: conquering the cell surface.
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.
Sidera
Katerina
K
Department of Biochemistry, Hellenic Pasteur Institute, Athens, Greece.
Patsavoudi
Evangelia
E
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002465:Cell Movement / Q000502:physiology*; D019281:Dimerization; D005109:Extracellular Matrix / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3
D000911:Antibodies, Monoclonal; D018841:HSP90 Heat-Shock Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C520254:4C5 monoclonal antibody; C508053:ERBB2 protein, human