Project: Research project

Project Details


Cell motility plays a central role in a wide variety of normal and
pathological processes. Examples of cell motility in the nervous system
include the movement of growth cones and the migration of neuroblasts and
glial cells that occur in development. A striking example of how
motility leads to disease can be seen in malignant gliomas. Cells from
these tumors migrate considerable distances from the primary site,
sometimes crossing from one cerebral hemisphere to the other. It is
likely that motility is important in making these tumors so invasive and
difficult to treat.
There is a growing body of evidence that two cytoskeletal
proteins--actin and myosin--compose the motor that drives motility.
Myosins can be divided into two groups, called myosins I and II. These
two forms of myosin are found in different regions of motile cells, and
they clearly have different roles. These different functions must be
reflected in differences in enzymology, structure, and mechanism of
Data to be presented in this application will show that myosin I and
II isoforms are present in several primary CNS malignancies, including
gliomas. I will propose in this application to first expand on this
observation by screening a wider variety of glioma cell lines as well as
developing, embryonic brain in order to see if both myosin isoforms are
present. I will also examine the intracellular distribution of these
isoforms and their response to motility-stimulating growth factors.
Second, I will isolate myosins I and II and measure the rate and
equilibrium constants that describe their interactions with actin and
ATP. Finally, I will examine the unique structural aspects of myosin I
in detail, using a variety of biochemical and biophysical techniques.
These latter experiments will use myosins I and II from Acanthameoba
castellanii, a unicellular motile organism, as this source can provide
quantities of protein large enough to perform the measurements that I
propose. The high degree of sequence homology between Acanthamoeba
myosins I and II and their vertebrate counterparts means that these
experiments should allow me to make valid conclusions about CNS and
glioma myosins.
Results of these studies will be used to construct a detailed
molecular model of how the actin-myosin interaction produces motility.
These studies may ultimately allow the development of pharmacologic
modulators of cell motility that could alter the biological
aggressiveness of malignant glial tumors.
StatusNot started


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