Genomes and Genes
INTERMEDIATE FILAMENT CELL SURFACE INTERACTIONS
Principal Investigator: Robert D Goldman
Abstract: We propose to study the role of intermediate filaments (IF) in cell shape and motility. Our overarching hypothesis is that alterations in the assembly states and mechanical properties of cytoskeletal IF, specifically the type III IF composed of vimentin, play important roles in regulating the locomotory behavior of mesenchymal cells such as fibroblasts. These studies are important as IF are major elements of the cytoskeletal system of mammalian cells and yet their specific functions in cell motility remain unknown. Our specific aims are to determine the functions of vimentin IF in the formation of the lamellipodium/lamella that plays a major role in cell locomotion. Specifically we will study the changes in the assembly states and mechanical properties of vimentin IF that accompany the formation of lamellipodia. We will also determine the role that phosphorylation plays in the changes in vimentin organization that accompany the formation of lamellipodia and the initiation of cell motility. Live cell imaging of vimentin IF will involve the use of quantitative fluorescence speckle microscopy (qFSM) in order to begin to determine the nature of IF assembly, subunit exchange and their movements within cells. Other experiments are aimed at determining the changes in the mechanical properties of vimentin IF that accompany cell motility. PUBLIC HEALTH RELEVANCE: Intermediate Filaments (IF) are structural proteins that are involved in determining cell shape, cell movement, mechanical integrity, and nuclear architecture. However, their specific functions remain unknown. We propose basic studies aimed at understanding their specific functions in the movement and mechanical properties of cells. These basic studies of the structure and function of IF will not only provide insights into understanding their normal functions, but also in determining their defective functions in the many diseases attributed to mutations in the genes encoding the different types of IF proteins.
Funding Period: ----------------1986 - ---------------2011-
more information: NIH RePORT
- Assembling an intermediate filament network by dynamic cotranslationLynne Chang
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
J Cell Biol 172:747-58. 2006..The results show that the motility and targeting of peripherin mRNPs, their translational control, and the assembly of an IF cytoskeletal system are linked together in a process we have termed dynamic cotranslation...
- Intermediate filaments: versatile building blocks of cell structureRobert D Goldman
Department of Cell and Molecular Biology, Northwestern University s Feinberg School of Medicine, Chicago, IL 60611, USA
Curr Opin Cell Biol 20:28-34. 2008..IF also play a role in the organization of organelles by modulating their motility and providing anchorage sites within the cytoplasm...
- Micromechanical properties of keratin intermediate filament networksSivaraj Sivaramakrishnan
Department of Biomedical Engineering, Northwestern University, 2145 North Sheridan Road, Evanston, IL 60208, USA
Proc Natl Acad Sci U S A 105:889-94. 2008..The high storage modulus of the KIF network, coupled with its solid-like rheological behavior, supports the role of KIF as an intracellular structural scaffold that helps epithelial cells to withstand external mechanical forces...
- Ubiquitin-proteasome-mediated degradation of keratin intermediate filaments in mechanically stimulated A549 cellsAriel Jaitovich
Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, 240 East Huron, Chicago, IL 60611, USA
J Biol Chem 283:25348-55. 2008..These data suggest that shear stress promotes the disassembly and degradation of the keratin IF network via phosphorylation and the ubiquitin-proteasome pathway...
- Insights into the mechanical properties of epithelial cells: the effects of shear stress on the assembly and remodeling of keratin intermediate filamentsEric W Flitney
Department of Cell and Molecular Biology, Feinberg School of Medicine of Northwestern University, 303 E Chicago Avenue, Chicago, IL 60611, USA
FASEB J 23:2110-9. 2009..We suggest that keratin particles constitute a reservoir of protein that can be recruited into KIFs under flow, creating a more robust cytoskeleton able to withstand shear forces more effectively...
- Ubiquitin is a novel substrate for human insulin-degrading enzymeLuis A Ralat
Ben May Department for Cancer Research, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA
J Mol Biol 406:454-66. 2011..Together, our studies link the control of Ub clearance with IDE...
- Vimentin organization modulates the formation of lamellipodiaBrian T Helfand
Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Mol Biol Cell 22:1274-89. 2011..These findings demonstrate an antagonistic relationship between VIF and the formation of lamellipodia...
- Vimentin intermediate filaments modulate the motility of mitochondriaOxana E Nekrasova
Group of Cell Biology, Institute of Protein Research, Russian Academy of Sciences, Moscow 119988, Russia
Mol Biol Cell 22:2282-9. 2011..It was also found that a vimentin peptide consisting of residues 41-94 localizes to mitochondria. Taken together, these data suggest that VimIFs bind directly or indirectly to mitochondria and anchor them within the cytoplasm...
- Inroads into the structure and function of intermediate filament networksRobert D Goldman
Department of Cell and Molecular Biology, Northwestern University s Feinberg School of Medicine, 303 E Chicago Avenue, Chicago, IL 60611, USA
J Struct Biol 177:14-23. 2012..Many of our advances in understanding IF are based on conversations with Ueli which have taken place during adventurous and sometimes dangerous hiking and biking trips throughout the world...