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Principal Investigator: MARGARET A TITUS
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2021
Award: $194,118
Funding agency: National Institute of General Medical Sciences
Administrative Supplement for Equipment - GM122917
Margaret A. Titus, PI
Abstract of Parent Project
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 are found in a wide variety of cell types such as neurons
that use them for gradient sensing and efficient directional migration and 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 the parent project 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, c) identify proteins that interact with the MF myosin to promote cortical targeting
during filopod initiation and filopod tip formation and d) 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 the parent 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 enable directed migration or invasion of surrounding tissues.
Terms: <3-D><3-Dimensional><3D><Actin Filaments><Actin-Activated ATPase><Actins><Administrative Supplement><Biologic Models><Biological Models><Body Tissues><Cell Body><Cells><Computer Models><Computerized Models><Dictyostelium><Environment><Equipment><Filopodia><Goals><In Vitro><Invaded><Knowledge><Length><Malignant Cell><Membrane><Microfilaments><Model System><Modeling><Molecular><Motor><Myofilaments><Myosin A><Myosin ATPase><Myosin Adenosine Triphosphatase><Myosin Adenosinetriphosphatase><Myosin IIA><Myosins><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Non-Muscle Myosin Type IIA><Nonmuscle Myosin Type IIA><Process><Property><Proteins><Role><Structure><Tail><Tissues><VASP><Work><base><cancer cell><cancer invasiveness><cell type><computational modeling><computational models><computer based models><computerized modeling><cross-link><crosslink><ezrin><in silico><in vivo><membrane structure><membrane-organizing extension spike protein><migration><moesin><neuronal><parent project><phosphoprotein p81><polymerization><radixin><radixin protein><social role><therapeutic agent development><therapeutic development><three dimensional><tumor><vasodilator-stimulated phosphoprotein>