Extracellular heat shock protein HSP90beta secreted by MG63 osteosarcoma cells inhibits activation of latent TGF-beta1.
Transforming growth factor-beta 1 (TGF-beta1) is secreted as a latent complex, which consists of latency-associated peptide (LAP) and the mature ligand. The release of the mature ligand from LAP usually occurs through conformational change of the latent complex and is therefore considered to be the first step in the activation of the TGF-beta signaling pathway. So far, factors such as heat, pH changes, and proteolytic cleavage are reportedly involved in this activation process, but the precise molecular mechanism is still far from clear. Identification and characterization of the cell surface proteins that bind to LAP are important to our understanding of the latent TGF-beta activation process. In this study, we have identified heat shock protein 90 beta (HSP90beta) from the cell surface of the MG63 osteosarcoma cell line as a LAP binding protein. We have also found that MG63 cells secrete HSP90beta into extracellular space which inhibits the activation of latent TGF-beta1, and that there is a subsequent decrease in cell proliferation. TGF-beta1-mediated stimulation of MG63 cells resulted in the increased cell surface expression of HSP90beta. Thus, extracellular HSP90beta is a negative regulator for the activation of latent TGF-beta1 modulating TGF-beta signaling in the extracellular domain.
Suzuki
Shigeki
S
Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Kulkarni
Ashok B
AB
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; D016212:Transforming Growth Factor beta