Role of high molecular weight immunophilins in the subcellular localization of signalling proteins

GALIGNIANA, M.D.

Rosario

Conferencia; XLII Reunión Anual de SAIB; 2006

SAIB

Most soluble proteins are not confined to the cytoplasm or the nucleus in a static manner. They are able of shuttling dynamically through the nuclear pore, even when the number of molecules in a given compartment is overwhelmingly larger than the number located in the other compartment. Protein mistargeting has dire cellular consequences and leads to a large variety of pathologies. More than 300 diseases have been related to date with failures in the transport or mislocalization of proteins. As such, a major unsolved problem in Cell Biology that pertains to all signalling pathways relates to how these factors move to their sites of action. Corticosteroid receptors are superb tools for studying this conundrum. They are primarily cytoplasmic in the absence of ligand and rapidly move towards the nucleus upon hormone binding. A classical model proposed 25 years ago posited the notion that the hsp90-based heterocomplex associated to the steroid receptor must dissociate to allow its nuclear translocation, simple diffusion being the driving force. Although heuristic, this model has no experimental support. We provide direct evidence that the hsp90-high MW immunophilin complex bound to steroid receptors is not dissociated at early times upon ligand binding. Actually, it is required for the active retrograde movement of the receptor, a property also shared by other soluble factors such as p53.