Cell surface Cdc37 participates in extracellular HSP90 mediated cancer cell invasion.
Cdc37 is a 50 kDa molecular chaperone which targets intrinsically unstable protein kinases to the molecular chaperone HSP90. It is also an over-expressed oncoprotein that mediates carcinogenesis and maintenance of the malignant phenotype by stabilizing the compromised structures of mutant and/or over-expressed oncogenic kinases. Here we report that Cdc37 is not restricted intracellularly but instead it is also present on the surface of MDA-MB-453 and MDA-MB-231 human breast cancer cells, where it is shown to participate in cancer cell motility processes. Furthermore, we demonstrate using an anti-Cdc37 cell impermeable antibody, that similarly to its intracellular counterpart, this surface pool of Cdc37 specifically interacts with HSP90 as well as the kinase receptors HER2 and EGFR on the cell surface, probably acting as a co-factor in HSP90's extracellular chaperoning activities. Finally, we show that functional inhibition of surface HSP90 using mAb 4C5, a cell impermeable monoclonal antibody against this protein, leads not only to disruption of the Cdc37/HSP90 complex but also to inhibition of the Cdc37/ErbB receptors complexes. These results support an essential role for surface Cdc37 in concert with HSP90 on the cell surface during cancer cell invasion processes and strengthen the therapeutic potential of mAb 4C5 for the treatment of cancer.
Department of Biochemistry, Hellenic Pasteur Institute, Athens, Greece.
Avraam
A
El Hamidieh
Nicholas
N
Grammatikakis
Evangelia
E
Patsavoudi
D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D001943:Breast Neoplasms / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D018833:Chaperonins / Q000276:immunology / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018797:Cell Cycle Proteins; D018833:Chaperonins; D066246:ErbB Receptors; D018841:HSP90 Heat-Shock Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C498362:CDC37 protein, human