The goal of the proposed research is to understand how the cytoskeleton is organized for differentiated function, and in what ways that organization is disrupted in cancer cells. Particular attention is paid to the structure and function of the membranecytoskeleton connection. The proposed research takes advantage of several animal cell models for differentiation and oncogenic transformation to identify molecules that may be crucial for the changes occur upon differentiation and which may also be the targets of transforming genes. A major focus of these experiments is an analysis of the functions of an ezrin-related protein. We have shown that this protein has properties of both a microtubule and a microfilament-associated protein. For example, it localizes to growth cones in a manner similar but not identical to that of F-actin. But its position at the growth cone in turn depends upon intact microtubules. These results and others suggest that this protein may interact with both of these two cytoskeletal elements. Ezrin itself is a substrate for kinases associated with oncogenic transformation and growth factors. In addition, the DNA sequence of ezrin suggests that it has a membrane binding domain. Taken together, these findings suggest that ezrin may play a crucial role in mediating the connections between the cytoskeleton and the plasma membrane connection. A range of results argues that the membrane-cytoskeleton connection is modified upon oncogenic transformation, and play an important role in the expression of differentiated cell morphology and which may mediate the loss of that morphology that occurs upon transformation. Part of the proposed research is designed to analyze these interactions, and their dependence upon transformation and differentiation, in detail. In related work, other experiments are designed to identify those molecules which are essential for the expression of differentiated cytoskeletal organization, and to design and apply rigorous tests for their function.
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