Skip to content Skip to navigation

Thrombin receptor signaling to cytoskeleton requires Hsp90.

TitleThrombin receptor signaling to cytoskeleton requires Hsp90.
Publication TypeJournal Article
Year of Publication2001
AuthorsPai, K S., Mahajan V B., Lau A, and Cunningham D D.
JournalJ Biol Chem
Date Published2001 Aug 31
KeywordsAnimals, Animals, Newborn, Astrocytes, Cells, Cultured, Cerebral Cortex, Cloning, Molecular, Cytoskeleton, HSP90 Heat-Shock Proteins, Humans, Neurons, Oligodeoxyribonucleotides, Antisense, Rats, Rats, Sprague-Dawley, Receptor, PAR-1, Receptors, Thrombin, Recombinant Fusion Proteins, rhoA GTP-Binding Protein, Saccharomyces cerevisiae, Signal Transduction, Thrombin

Thrombin is a serine protease that evokes various cellular responses involved in injury and repair of the nervous system through the activation of protease-activated receptor-1 (PAR-1). Signals that modulate cell morphology precede most PAR-1 effects, but the initial signal transduction molecules are not known. Using the yeast two-hybrid system, we identified Hsp90, a chaperone with known signaling properties, as a binding partner of PAR-1. The interaction was confirmed by glutathione S-transferase pull-down, overlay, and co-immunoprecipitation assays. Morphological assays in mouse astrocytes were carried out to evaluate the importance of Hsp90 during cytoskeletal signaling. Reducing Hsp90 levels by antisense treatment or disruption of the Hsp90.PAR-1 complex by the Hsp90-specific drug geldanamycin attenuated thrombin-mediated astrocyte shape changes. Furthermore, overexpression of the PAR-1 cytoplasmic tail abrogated thrombin-induced cytoskeletal changes in neuronal cells. Treatment with geldanamycin specifically inhibited activation of RhoA without affecting thrombin-mediated intracellular calcium release, revealing the regulation of a distinct signaling pathway by Hsp90. Taken together, these studies demonstrate that Hsp90 may be essential for PAR-1-mediated signaling to the cytoskeleton.

Alternate JournalJ. Biol. Chem.
PubMed ID11413145
Grant ListAG00538 / AG / NIA NIH HHS / United States