Chaperones, immunophilins and nuclear receptor shuttling

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DESCRIPTION (provided by applicant): Although movement of proteins comprised in vesicles is known to occur on cytoskeletal tracts, the movement of non-vesicle associated proteins is unknown. Soluble proteins such as MAPKs, STATs, p53, NFkB, steroid receptors, cyclins, etc. are not confined to the cytoplasm or the nucleus in a static manner, but are capable of shuttling dynamically through the nuclear pore even when the number of molecules in a given compartment is overwhelmingly larger than the small number located in the other compartment. Moreover, it has always been posited that soluble proteins move by diffusion. Protein mistargeting has dire cellular consequences and leads to a large variety of pathologies, including cancer. In this regard, more than 200 diseases have been related with failures in the transport or mislocalization of proteins. Therefore, a major unsolved problem that pertains to all signaling pathways relates to how proteins move to their sites of action. Corticosteroid receptors constitute an excellent system for studying protein movement. They are primarily located in the cytoplasm in the absence of ligand and rapidly move towards the nucleus with ligand. The classical model supports the notion that, upon steroid binding, the hsp90-immunophilin (IMM)-heterocomplex dissociates from the receptor, which permits its nuclear translocation. Here, we challenge this unproven model and postulate that the hsp90-IMM complex is required for receptor movement through the cytoplasm and also affects its function in the nucleus. Inasmuch as the ligand-receptor complex is a functional unit, the effect of ligand-binding on the regulation of receptor movement will also be studied. Therefore, the specific aims of this project are to determine: a) how proteins associated to the receptor-hsp90 heterocomplex regulate receptor movement, b) if proteins that belong to the hsp90-IMM heterocomplex are required for the nuclear translocation step of steroid receptors through the nuclear pore complex, c) the factor/s that can regulate the receptor anchorage to the nuclear matrix and the nuclear export step.