Eugene Marcantonio, M.D., Ph.D.
Cell adhesion and signaling via integrin receptors
Research in my lab is focused on the adhesive interactions of cells via integrin receptors with extracellular matrices and basement membranes. Integrins comprise a large family of cell surface receptors that function in adhesion in many cell types and are important in a wide variety of biological processes, including embryogenesis, cell migration, wound healing, malignant transformation, and metastasis. These transmembrane glycoproteins are heterodimers with distinct a and b subunits. Each a/b combination has a distinct specificity, binding a variety of matrix molecules, including laminin, fibronectin, and collagen .
We have been studying the structure and functions of integrins and their role in cell growth. Most of the work in the lab uses the integrin a1/b1, which is an induced receptor for laminin and collagen on lymphocytes. Induction in T cells occurs after activation in vitro and in vivo in rheumatoid arthritis, where a1+ T cells in the inflamed joints bind and invade tissue. One project in the lab is to understand the structure and function of cytoplasmic domains of in-tegrins. We have recently shown that both cytoplasmic domains of these receptors may be controlling integrin intracellular function. We are currently using dominant negative mutations and other techniques to identify the molecules which bind to integrin cytoplasmic domains. This structure-function analysis has led to the discovery of the mechanism by which integrins provide signals for anchorage dependent growth. This mechanism involves the recruitment of the adapter protein Shc, which then leads to a co-stimulation of the Ras pathway with growth factor receptors.
Current work in the lab is focused on three distinct areas. One focus is to determine both the molecular link between integrins and Shc, and which tyrosine kinases are involved. A second area is to determine the role of this signaling in the phenotypic modulation of vascular smooth muscle cells. A third area is to investigate the role of integrin signaling in the development and function of T lymphocytes. This last area utilizes a transgenic mouse model, which we have developed. Using a thymocyte -specific promoter, transgenic mice express a dominant negative form of integrin in developing T cells. These mice have partial blockades at two stages of T cell develop-ment. We are using this system to study integrin signaling in autoimmune diseases.
Smilenov LB, Mikhailov A, Pelham RJ, Marcantonio EE, Gundersen GG. 1999. Focal adhesion motility revealed in stationary fibroblasts. Science. 286(5442):1172-4.
David FS, Zage PE, Marcantonio EE. 1999. Integrins interact with focal adhesions through multiple distinct pathways. J Cell Physiol . 181(1):74-82.
Assoian RK, Marcantonio EE. 1997 The extracellular matrix as a cell cycle control element in atherosclerosis and restenosis. J Clin Invest. 100(11 Suppl):S15-8.
Marcantonio EE, David FS. 1997. Integrin receptor signaling: the propagation of an alpha-helix model. Matrix Biol. 16(4):179-84.
Wary KK, Mainiero F, Isakoff SJ, Marcantonio EE, Giancotti FG. 1996. The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Cell. 87(4):733-43.