Mechanisms Regulating the Kinetics and Specificity of Nuclear-Cytoplasmic Transport

About This Grant

PROJECT SUMMARY/ABSTRACT Nuclear-cytoplasmic transport governs communication between the cytoplasm and the nucleus and thus plays a pivotal role in the regulation of many fundamental cellular processes, including cell signaling, gene regulation, and cell cycle control. The nuclear pore complex (NPC) is one of the core components of the transport machinery and serves as the permeability barrier for macromolecular trafficking across the nuclear envelope. Given its housekeeping role as the gateway for nuclear-cytoplasmic transport, the NPC has been viewed as a relatively invariant structure across cell types. However, emerging evidence, including our own work, challenges this view and shows that NPCs exhibit profound variation in their number, post-translational modifications, and protein composition in different cellular and developmental contexts. Yet, we do not currently understand the mechanistic basis for how these changes in NPC state are regulated, nor how they influence cellular processes and cell physiology. The research proposal in this MIRA application will focus on the following three questions to define the emerging regulatory dimension of NPC function and their functional consequences on cell physiology. Over the next five years, we will: 1) determine how changes in NPC number modulate the kinetics and specificity of nuclear- cytoplasmic transport and control early embryogenesis; (2) define how NPC phosphorylation during interphase serves as part of cell signaling pathways to control nuclear-cytoplasmic transport and cell proliferation; and (3) dissect the mechanisms for assembly and regulation of cell type-specific NPC compositions during cell differentiation. Varied systems will be employed, including Drosophila embryos, mammalian tissue culture cells, and in vitro reconstitution systems, to best address the questions at hand. These projects will further the long- term goal of defining the role of the NPC as more than just a housekeeping transport apparatus but as an active regulator of cellular processes and physiology.