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Principal Investigator: MARGARET A TITUS
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2019
Award: $357,741
Funding agency: National Institute of General Medical Sciences
Cells migrating in tissues, including cancer cells, use filopodia to guide them through the 3D environment and increased formation of filopodia correlates strongly with the metastatic potential and invasiveness of cancer cells. Filopodia are slender actin-filled projections composed of a core of cross-linked, parallel actin bundles. They are highly dynamic, vary in length and found in a wide variety of cell types such as neurons that use them for gradient sensing and efficient directional migration or cancer cells that employ them for moving out from tumors into neighboring tissue.
The first steps of filopodia formation are not well understood. Three conserved proteins are required for their formation - a MyTH4-FERM myosin (MF; MyTH4 = myosin tail homology 4; FERM = band 4.1, ezrin, radixin, moesin) and two regulators of actin polymerization, VASP and Formin. How the action of these three proteins is coordinated to initiate filopodia formation is unknown. The objective of this proposal is to define the molecular mechanism of filopodia initiation with an emphasis on the role of a MF myosin in this process. The versatile model system, Dictyostelium will be used to define how a MF myosin and VASP work together to organize the fast growing ends of actin filaments at the membrane to initiate polymerization. A combination of in vivo, in vitro and in silico approaches will be employed to a) determine the functional relationship between a MF myosin, VASP and formin, b) identify the specific properties of the myosin motor used for filopodia initiation, and c) develop a stochastic computational model with predictive power that will inform the experimental goals, the results of which will be used to refine the model.
The knowledge generated by this project will reveal how cells use a myosin-based motor to build specific actin-based structures such as filopodia. Understanding how initiation occurs will also reveal how cells control filopodia formation to undergo directed migration or invade into surrounding tissues.
Terms: <3-D><3-Dimensional><3D><Actin Filaments><Actin-Activated ATPase><Actins><Affect><Amoeba><Amoeba genus><Assay><Binding><Binding Proteins><Bioassay><Biochemical><Biologic Assays><Biologic Models><Biological Assay><Biological Models><Body Tissues><Bundling><Cell Body><Cell Components><Cell Locomotion><Cell Migration><Cell Movement><Cell Structure><Cells><Cellular Migration><Cellular Motility><Cellular Structures><Chimera><Chimera organism><Collaborations><Computer Models><Computer Simulation><Computer based Simulation><Computerized Models><Cytoskeletal Gene><Cytoskeletal Proteins><DNA><Deoxyribonucleic Acid><Dictyostelium><Dictyostelium discoideum><Environment><Epithelial><Event><Evolution><Filopodia><Goals><Human><In Vitro><Invaded><Knowledge><Length><Ligand Binding Protein><Ligand Binding Protein Gene><Locomotor Activity><Malignant Cell><Mammalian Cell><Mathematical Model Simulation><Mathematical Models and Simulations><Mediating><Membrane><Microfilaments><Model System><Modeling><Modern Man><Molecular><Molecular Interaction><Motility><Motor><Motor Activity><Myofilaments><Myosin A><Myosin ATPase><Myosin Adenosine Triphosphatase><Myosin Adenosinetriphosphatase><Myosin IIA><Myosins><Nature><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Non-Muscle Myosin Type IIA><Nonmuscle Myosin Type IIA><Organism><Pathway interactions><Polymers><Power stroke><Process><Property><Protein Binding><Proteins><Role><Structure><Tail><Test Result><Tissues><VASP><Work><axon growth cone guidance><axon guidance><axonal guidance><base><bound protein><cancer cell><cancer invasiveness><cell motility><cell type><cohort><computational modeling><computational models><computational simulation><computer based models><computerized modeling><computerized simulation><cross-link><crosslink><experiment><experimental research><experimental study><ezrin><in silico><in vitro Assay><in vivo><in vivo evaluation><in vivo testing><insight><live cell image><live cell imaging><live cellular image><live cellular imaging><living system><membrane structure><membrane-organizing extension spike protein><migration><moesin><neuronal><pathway><phosphoprotein p81><polymerization><radixin><radixin protein><recruit><scaffold><scaffolding><social><social role><therapeutic agent development><therapeutic development><tumor><vasodilator-stimulated phosphoprotein><virtual simulation>