Subcellular movement of signaling molecules: how and why?

Abstract

The biological function of proteins is determined by their cellular localization and subsequent interactions with other factors within a given subcellular compartment. Therefore, it is critical to understand how proteins move to and from the sites where they exert biological effects and how this mechanism of movement is regulated. This concept becomes particularly interesting when soluble signalling factors such as STATs, p53, NFkB, MAPKs, C/EBPs, steroid receptors or cyclins are involved. Soluble proteins are not confined to the cytoplasm or the nucleus in a static manner, but they shuttle dynamically between subcellular compartments regardless of where they are primarily localized under certain biological conditions. Consistent with this concept ─and not surprisingly─protein mistargeting leads to a number of pathologies. Ideally, most of these pathologies could be attenuated or even prevented if we were able to regulate the subcellular localization of those mistargeted proteins; i.e. by interfering with the molecular machinery for protein movement and/or by regulating the function of anchoring factors of a given compartment. Nowadays, we know no more than the basics about regulatory mechanisms for protein anchoring, so we still have more questions and doubts than answers and certainties. On the other hand, the molecular mechanism by which soluble proteins move in the cell is an unsolved biological conundrum. In this regard, movement has always been assumed to occur in a stochastic manner by simple diffusion. This oversimplified model has been accepted as the driving mechanism for protein movement in both the cytoplasm and the nucleus. Although heuristic, this notion contradicts the concept of efficiency for protein targeting and, even more importantly, it collides against the concepts of cellular compartmentalization and specificity of action of signalling proteins. In this chapter we describe a novel model in which the cytoplasmic movement of some members of the nuclear receptor superfamily is regulated by their association with high molecular weight immunophilins. Based on their subnuclear distribution in different conditions, we also reformulate some classical concepts about the functional regulation of archetype hormone-regulated transcription factors such as steroid receptors and C/EBPs, and postulate the existence of a non-random mechanism for intranuclear trafficking of proteins.