Role of hsp90 and the hsp90-binding immunophilins in signalling protein movement.
The ubiquitous protein chaperone hsp90 has been shown to regulate more than 100 proteins involved in cellular signalling. These proteins are called 'client proteins' for hsp90, and a multiprotein hsp90/hsp70-based chaperone machinery forms client protein.hsp90 heterocomplexes in the cytoplasm and the nucleus. In the case of signalling proteins that act as transcription factors, the client protein.hsp90 complexes also contain one of several TPR domain immunophilins or immunophilin homologs that bind to a TPR domain binding site on hsp90. Using several intracellular receptors and the tumor suppressor p53 as examples, we review evidence that dynamic assembly of heterocomplexes with hsp90 is required for rapid movement through the cytoplasm to the nucleus along microtubular tracks. The role of the immunophilin in this system is to connect the client protein.hsp90 complex to cytoplasmic dynein, the motor protein for retrograde movement toward the nucleus. Upon arrival at the nuclear pores, the receptor.hsp90.immunophilin complexes are transferred to the nuclear interior by importin-dependent facilitated diffusion. The unliganded receptors then distribute within the nucleus to diffuse patches from which they proceed in a ligand-dependent manner to discrete nuclear foci where chromatin binding occurs. We review evidence that dynamic assembly of heterocomplexes with hsp90 is required for movement to these foci and for the dynamic exchange of transcription factors between chromatin and the nucleoplasm.
Pratt
William B
WB
Department of Pharmacology, University of Michigan Medical School, 1301 Med. Sci. Res. Building III, Ann Arbor, MI 48109-0632, USA. mgali@umich.edu
Galigniana
Mario D
MD
Harrell
Jennifer M
JM
DeFranco
Donald B
DB
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D020104:Immunophilins / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D016159:Tumor Suppressor Protein p53; D020104:Immunophilins