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 . 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 p50(cdc37). The immunophilins bind to a single TPR acceptor site on hsp90, and p50(cdc37) binds to an adjacent site so that binding is exclusive for p50(cdc37) or an immunophilin. Direct interaction of immunophilins with the transcription factors or p50(cdc37) 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 p50(cdc37) target, respectively, the retrograde or anterograde direction of signalling protein movement by functioning as connectors that link the signalling proteins to the movement machinery. (C) 1999 Elsevier Science Inc. All rights reserved.