Mark H. Ginsberg
Professor of Medicine
M.D., State University of New York
The interactions between cells and their surrounding extracellular matrix
play a central role in the development of multi-cellular animals. We study
integrins, receptors for these matrix proteins. Many integrins recognize
short peptide sequences in proteins such as fibrinogen and fibronectin.
These peptides can therefore inhibit integrin function and represent
prototypes of a novel class of therapeutics. Integrin receptors transmit
information in both directions across the plasma membrane via their
cytoplasmic domains. For example, the anchorage dependence of cell growth
and cell migration are mediated by signals emanating from integrins. We
therefore use reverse genetics in cells and in mice to study key components
of the integrin signaling pathways that control cell migration, survival,
and growth and how dysregulation of these pathways can contribute to cancer
Conversely, intracellular signaling events can change the conformation and ligand binding affinity of integrin receptors. This process, termed "inside-out" signal transduction, seems to be a general property of this receptor family. Inside-out signaling controls adhesive functions, cell migration and the assembly of an extracellular matrix. To understand the structure of the cytoplasmic domains and how they interact with intracellular partners to transmit signals to and from integrins, we've utilized a combination of synthetic and recombinant approaches to generate model protein mimics of the integrin cytoplasmic domains. Through the use of these model proteins the interactions of integrins with the actin cytoskeleton and signaling enzymes have been uncovered. Furthermore, a specific interaction of integrin cytoplasmic domains with talin, a cytoskeletal protein, proved to be the key to inside out signaling. Our present focus is to analyze the structural basis of inside out signaling, how the signal traverses the plasma membrane, and how cells regulate the talin-integrin interaction.