This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Communication between the nucleus and the cytoplasm is mediated by large proteinaceous structures embedded in the nuclear envelope, the nuclear pore complexes (NPCs). The long-term goal of this project is to elucidate the molecular sequence of events required for translocation through the NPC. We hypothesize that the shuttling transport factors and a family of NPC proteins that contain regions with multiple FG-type repeats (F, phenylalanine;G, glycine). We also propose that key events for regulation of mRNA export directionality are controlled at the NPC by the action of multiple factors. To analyze the mechanism and regulation of mRNA transport through the NPCs, we propose the following.
In aims one and two, we will build on our recent results documenting the first in vivo tests of NPC translocation models. We propose to use S. cerevisiae mutants with minimal repertoires of the FG binding sites for mRNA transport factors. To define the requirements for FG repeat numbers, FG types and critical FG binding sites in the NPC substructural locations, the mutants will be assayed for mRNA export defects. A biochemical approach will be used in aim two to detect changes in protein-protein interactions during the extrusion of the mRNA-protein complex through the NPC.
In aim three, we will investigate the mechanism for activation of the DEAD-box helicase Dbp5 by the essential mRNA export factor Gle1 and production of the soluble inositol hexakisphosphate (IP6). This proposal represents an area of basic science research that has the potential to provide novel insights into multiple disease processes. Transport factors and NPC proteins are targets for viral inhibition of cell function and mediators of viral mRNA export. Inositol signaling defects are associated with disease states including cancer cell growth, inflammation, neurotransmission, and organ development. Knowledge of the NPC translocation mechanism will be key for designing therapeutic strategies to selectively target these pathways.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CB-H (40))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
Schools of Medicine
United States
Zip Code
Xavier, Marina Amaral; Tirloni, Lucas; Pinto, Antônio F M et al. (2018) A proteomic insight into vitellogenesis during tick ovary maturation. Sci Rep 8:4698
Hollmann, Taylor; Kim, Tae Kwon; Tirloni, Lucas et al. (2018) Identification and characterization of proteins in the Amblyomma americanum tick cement cone. Int J Parasitol 48:211-224
Stieg, David C; Willis, Stephen D; Ganesan, Vidyaramanan et al. (2018) A complex molecular switch directs stress-induced cyclin C nuclear release through SCFGrr1-mediated degradation of Med13. Mol Biol Cell 29:363-375
Seixas, Adriana; Alzugaray, María Fernanda; Tirloni, Lucas et al. (2018) Expression profile of Rhipicephalus microplus vitellogenin receptor during oogenesis. Ticks Tick Borne Dis 9:72-81
Wang, Zheng; Wu, Catherine; Aslanian, Aaron et al. (2018) Defective RNA polymerase III is negatively regulated by the SUMO-Ubiquitin-Cdc48 pathway. Elife 7:
Luhtala, Natalie; Aslanian, Aaron; Yates 3rd, John R et al. (2017) Secreted Glioblastoma Nanovesicles Contain Intracellular Signaling Proteins and Active Ras Incorporated in a Farnesylation-dependent Manner. J Biol Chem 292:611-628
Thakar, Sonal; Wang, Liqing; Yu, Ting et al. (2017) Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation. Proc Natl Acad Sci U S A 114:E610-E618
Jin, Meiyan; Fuller, Gregory G; Han, Ting et al. (2017) Glycolytic Enzymes Coalesce in G Bodies under Hypoxic Stress. Cell Rep 20:895-908
Ogami, Koichi; Richard, Patricia; Chen, Yaqiong et al. (2017) An Mtr4/ZFC3H1 complex facilitates turnover of unstable nuclear RNAs to prevent their cytoplasmic transport and global translational repression. Genes Dev 31:1257-1271
Ju Lee, Hyun; Bartsch, Deniz; Xiao, Cally et al. (2017) A post-transcriptional program coordinated by CSDE1 prevents intrinsic neural differentiation of human embryonic stem cells. Nat Commun 8:1456

Showing the most recent 10 out of 583 publications