Education and Training
Cambridge University, BA, Biochemistry
Cambridge University, PhD, Cell and Molecular Biology
Cold Spring Harbor Laboratory, Postdoc
Areas of Interest
We have been interested for many years in how cells adhere to extracellular matrix (ECM) and to other cells. Both types of adhesion involve specific cell adhesion molecules, most prominently integrins in cell-ECM adhesion, and cadherins as well as various Ig family members in cell-cell adhesion. These adhesion molecules provide sites of attachment for the cytoskeleton and their engagement activates multiple signaling pathways. Cell adhesion molecules are mechanosensitive, responding to physical forces that are either applied externally or generated internally by actomyosin contractility. Experimentally, we apply mechanical forces on cells using magnetic beads coated with ligands or antibodies that interact with specific cell adhesion molecules. Using magnets we can apply sustained tension on cells or apply short pulses of force and determine how cells respond. Many of the signaling pathways downstream from cell adhesion molecules affected by mechanical force involve members of the Rho GTPase family of regulatory proteins. These are activated by guanine nucleotide exchange factors (GEFs) and turned off by GTPase activating proteins (GAPs) that promote hydrolysis of bound GTP. GEFs and GAPs are themselves targeted by many signaling pathways. We are interested in which GEFs and GAPs are activated or inhibited in response to applying force to the different adhesion molecules and have developed techniques to identify active GEFs and GAPs in crude cell lysates.
In recent experiments we have found that isolated nuclei respond to mechanical force by stiffening. We have identified some of the signaling components involved. When stiffening of the nucleus is blocked by expression of dominant negative constructs, we find that this affects the behavior of the cell, the organization of its cytoskeleton and even its transcriptional profile. We are currently investigating how the nucleus affects the mechanical response of cells and how it contributes to the organization of the cytoskeleton.
Much of our work on cell-cell interactions involves endothelial cells (ECs), which line blood vessels. Not only do ECs interact with their neighbors but they also interact with leukocytes. EC junctions are very important in regulating the permeability of blood vessel walls to materials in the blood circulation. We are exploring the factors that regulate EC junctions. We are also interested in how leukocytes cross the endothelial barrier and are investigating the signaling pathways that leukocytes trigger in ECs to facilitate their passage through EC junctions or in some situations through the body of an EC. Again, many of the pathways we are investigating involve Rho GTPases, as well as their regulators, GEFs and GAPs.
Awards and Honors
Kenan Distinguished Professorship