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Principal Investigator: MARGARET A TITUS
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2024
Award: $83,758
Funding agency: National Institute of General Medical Sciences
Administrative Supplement for Equipment - GM122917
Margaret A. Titus, PI
Project Summary
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><Cell Locomotion><Cell Migration><Cell Movement><Cells><Cellular Migration><Cellular Motility><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><Polymers><Process><Property><Proteins><Role><Structure><Tail><Tissues><VASP><Work><cancer cell><cancer invasiveness><cell motility><cell type><computational modeling><computational models><computer based models><computerized modeling><crosslink><ezrin><in silico><in vivo><membrane structure><membrane-organizing extension spike protein><migration><moesin><neuronal><parent award><parent project><phosphoprotein p81><polymer><polymeric><polymerization><radixin><radixin protein><social role><therapeutic agent development><therapeutic development><three dimensional><tumor><vasodilator-stimulated phosphoprotein>