THE HSP90-BASED CHAPERONE SYSTEM - INVOLVEMENT IN SIGNAL-TRANSDUCTIONFROM A VARIETY OF HORMONE AND GROWTH-FACTOR RECEPTORS

A variety of transcription factors and protein kinases involved in sig nal transduction are recovered from cells in heterocomplexes containin g the abundant protein chaperone hsp90. Genetic studies in yeast have demonstrated that binding of steroid receptors, the dioxin receptor, a nd some protein kinases to hsp90 is critical for their signal transduc ing function in vivo. These heterocomplexes are formed by a multiprote in chaperone machinery consisting of at least four ubiquitous proteins -hsp90, hsp70, p60 and p23. Four high-molecular-weight immunophilins h ave been discovered as components of steroid receptor or other transcr iption factor complexes with hsp90. The immunophilins, protein chapero nes with prolyl isomerase activity, bind the immunosuppressant drugs F K506 or CyP-40. These immunophilins all bind via tetratricopeptide rep eat (TPR) domains to a single TPR binding site on each hsp90 dimer, an d multiple heterocomplexes exist for each protein chaperoned by hsp90 according to the immunophilin that is bound to this TPR binding site a t any time. Three components of the MAP kinase signalling system (Src, Raf, and Mek) exist in complexes with hsp90 and a 50-kDa protein that is the mammalian homolog of the yeast cell cycle control protein cdc3 7. The p50(cdc37) binds to hsp90 at a site that is close to but differ ent from the TPR binding site of the immunophilins, and like the immun ophilins, p50(cdc37) is thought to be involved in targeting and traffi cking of the protein kinases. The recent introduction of the benzoquin one antibiotic geldanamycin has facilitated the identification of prot eins that are chaperoned by the hsp90-based system. Geldanamycin binds to members of the hsp90 protein family, blocking assembly of hsp90 he terocomplexes and destabilizing preformed heterocomplexes. In the pres ence of geldanamycin, the function of hsp90-chaperoned proteins is dis rupted, and the proteins undergo rapid degradation by an ubiquitin-dep endent proteasomal mechanism. It is becoming clear that hsp90 chaperon ing is not only essential to a variety of signal transduction pathways , but is critical for proper folding, stabilization, and trafficking o f an expanding list of proteins.