A model for the cytoplasmic trafficking of signalling proteins involving the hsp90-binding immunophilins and p50cdc37.
A number of transcription factors and protein kinases involved in signal transduction exist in heterocomplexes with the ubiquitous and essential protein chaperone hsp90. These signalling protein x hsp90 heterocomplexes are assembled by a multiprotein chaperone system comprising hsp90, hsp70, Hop, hsp40, and p23. In the case of transcription factors, the heterocomplexes with hsp90 also contain a high molecular weight immunophilin with tetratricopeptide repeat (TPR) motifs, such as FKBP52 or CyP-40. In the case of the protein kinases, the heterocomplexes contain p50cdc37. The immunophilins bind to a single TPR acceptor site on hsp90, and p50cdc37 binds to an adjacent site so that binding is exclusive for p50cdc37 or an immunophilin. Direct interaction of immunophilins with the transcription factors or p50cdc37 with the protein kinases leads to selection of different heterocomplexes after their assembly by a common mechanism. Studies with the glucocorticoid receptor, for which translocation from the cytoplasm to the nucleus is under hormonal control, suggest that dynamic assembly of the heterocomplexes is required for rapid movement of the receptor through the cytoplasm along cytoskeletal tracts. As for the similar short-range trafficking of vesicles along microtubules, there must be a mechanism for linking the signalling protein solutes to the molecular motors involved in movement. We present here a model in which the immunophilins and p50cdc37 target, respectively, the retrograde or anterograde direction of signalling protein movement by functioning as connectors that link the signalling proteins to the movement machinery.
Pratt
W B
WB
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109, USA.
Silverstein
A M
AM
Galigniana
M D
MD
D000818:Animals; D016227:Benzoquinones; D001692:Biological Transport / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000502:physiology*; D018833:Chaperonins; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton / Q000502:physiology; D004058:Diffusion; D029721:Drosophila Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D020104:Immunophilins / Q000378:metabolism; D047029:Lactams, Macrocyclic; D046911:Macromolecular Substances; D008954:Models, Biological; D018832:Molecular Chaperones; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism
D016227:Benzoquinones; C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D046911:Macromolecular Substances; D018832:Molecular Chaperones; D011809:Quinones; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D014157:Transcription Factors; D011494:Protein Kinases; D018833:Chaperonins; D020104:Immunophilins; C001277:geldanamycin