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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA053395-03
Application #
3198132
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1991-01-01
Project End
1995-12-31
Budget Start
1993-01-01
Budget End
1993-12-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Type
Organized Research Units
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Gonzalez-Agosti, C; Solomon, F (1996) Response of radixin to perturbations of growth cone morphology and motility in chick sympathetic neurons in vitro. Cell Motil Cytoskeleton 34:122-36
Henry, M D; Gonzalez Agosti, C; Solomon, F (1995) Molecular dissection of radixin: distinct and interdependent functions of the amino- and carboxy-terminal domains. J Cell Biol 129:1007-22
Magendantz, M; Henry, M D; Lander, A et al. (1995) Interdomain interactions of radixin in vitro. J Biol Chem 270:25324-7
Wasco, W; Bupp, K; Magendantz, M et al. (1992) Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid beta protein precursor. Proc Natl Acad Sci U S A 89:10758-62