Hsp70 and Hsp90 oppositely regulate TGF-ß signaling through CHIP/Stub1.

ABSTRACT

Transforming growth factor-ß (TGF-ß) signaling plays an important role in regulation of a wide variety of cellular processes. Canonical TGF-ß signaling is mediated by Smads which were further regulated by several factors. We previously reported that E3 ubiquitin ligase CHIP (carboxyl terminus of Hsc70-interacting protein, also named Stub1) controlled the sensitivity of TGF-ß signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation. Here, we present evidence that Hsp70 and Hsp90 regulate the complex formation of Smad3/CHIP. Furthermore, we observed that over-expressed Hsp70 or inhibition of Hsp90 by geldanamycin (GA) leads to facilitated CHIP-induced ubiquitination and degradation of Smad3, which finally enhances TGF-ß signaling. In contrast, over-expressed Hsp90 antagonizes CHIP mediated Smad3 ubiquitination and degradation and desensitizes cells in response to TGF-ß signaling. Taken together, our data reveal an opposite role of Hsp70 and Hsp90 in regulating TGF-ß signaling by implicating CHIP-mediated Smad3 ubiquitination and degradation. This study provides a new insight into understanding the regulation of the TGF-ß signaling by chaperones.