We are also exploring the involvement of classical signaling cascades on chaperone-mediated signaling. The roles of the chaperones CHIP (carboxy-terminus of Hsc70-interacting protein) and Hsp90 (heat shock protein 90) are highly conserved throughout species and both proteins are critical for quality control and stress recovery systems in most cell types. CHIP is an ubiquitin ligase that is essential for mitigating stress-related proteins after a cellular stress response (1, 2) and has anti-apoptotic properties. Hsp90 has the unique ability to maintain mutated proteins in a folded and partially active state at the expense of ATP, permitting proteins that would otherwise be immediately targeted for degradation to persist within the cell. These proteins, referred to as clients, include a number of oncogenic and neurodegenerative associated proteins, such as ErbB2, mutant p53 and the tau protein, as well as critical components of breast cancer-related signaling pathways such as Akt. Small molecules aptly named Hsp90 inhibitors have been generated and functionally force these clients to be degraded through the proteasome (3-5). CHIP is a critical component for this degradation, and since it binds with both Hsp70 and Hsp90, it has an opportunity to interact with and ubiquitinate a number of proteins via their scaffold. Conversely, other chaperones and/or co-chaperones that are part of the complex at the time of the client/Hsp90 interaction can facilitate the ATPase activity of Hsp90, preserving the client substrate (6, 7). For example, tau and Akt degradation was prevented by deleting CHIP or Hsp90 (8), but tau degradation was enhanced by deleting prostaglandin E synthase 3 (P23), a co-chaperone that promotes re-folding or maintenance of Hsp90 clients. Therefore, we would like to investigate whether other co-chaperones may be involved with Akt and tau degradation. Perhaps identifying proteins that can facilitate the degradation of these proteins would provide novel targets to develop drugs that would reduce their levels rather than activity.