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Deanna S. Smith (Ph.D., Stanford University, 1994)
Assistant Professor
E-mail: deannasm@biol.sc.edu |
The regulation of cytoplasmic dynein by Lis1 and Nudel in development and disease.
Cells exhibit an array of behaviors that require movement - they establish polarity, divide, migrate, and undergo morphological changes necessary for specific functions. Molecular motors are emerging as critical components of many of these processes, and as such are likely to be tightly regulated. Indeed, several human diseases have been linked to problems with motor proteins. We recently reported that the Lis1 gene product activates a microtubule-based motor, cytoplasmic dynein, in a dose dependent manner. Loss or mutation of one allele of the Lis1 gene causes a severe developmental brain malformation, Classical Lissencephaly. Cytoplasmic dyneins are microtubule-associated ATPases that have been linked to membrane trafficking, organelle distribution, cytokinesis, and migration. Various models implicate Lis1 in many of these processes, so it seems likely that Lissencephaly is the result of inadequate dynein activity.We are interested in exploring if and how Lis1 (and an associated protein, Nudel) are influenced by signal transduction pathways to regulate dynein behavior. We already know that Nudel serves as a substrate for Cdk5, a serine/threonine kinase with a prominent role in cortical development, and we have evidence that phosphorylation of Nudel is important for axon transport. More recently we have uncovered a link between Lis1 and the small GTPase Rac1, a known CDK5 substrate recently implicated in microtubule-driven actin dynamics at leading edges in migrating cells. In addition, we have evidence to suggest Lis1 associates with proteins implicated in colon cancer. Obtaining a clearer view of if and how cytoplasmic dynein is regulated by these molecules should help us to understand how its deregulation might lead to disease. A multidisciplinary approach will be used that will include live cell imaging techniques.
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