Cancer Cell Biology
Area of interest
In the Burridge lab, we are interested in cell adhesion, cell migration and the regulation of cell behavior by Rho family GTPases. In terms of adhesion, we are interested in the adhesion cells make both to the extracellular matrix (ECM) and to other cells. Many cancer cells change their adhesive interactions, decreasing cell-cell interaction and increasing adhesion to the ECM. We are interested in the relationship between adhesion and migration. Again, tumor cells often become more invasive and display enhanced migratory characteristics.
Rho family GTPases are key regulators of adhesion, the cytoskeleton and many other aspects of cell behavior. We are studying several members of the Rho family, including RhoA, RhoC, Rac, Cdc42, RhoG and RhoE/Rnd3. In general, these Rho family proteins are active when they have GTP bound and are inactive when the GTP is hydrolyzed to GDP. Hydrolysis is catalyzed by an intrinsic GTPase activity and is stimulated by GTPase activating proteins (GAPs). RhoE is notable in lacking GTPase activity and being constitutively active. With the exception of RhoE, the other family members are activated by guanine nucleotide exchange factors (GEFs), which displace GDP and allow exchange for GTP. We are very interested in GEFs and GAPs and how these are regulated by various signaling pathways. For example, we know that RhoA activity is first turned off by integrin engagement and then is turned on. We have identified the pathway by which initial integrin-mediated adhesion depresses RhoA activity and shown that this involves the src pathway and phosphorylation and activation of p190RhoGAP. We are exploring how RhoA activity is subsequently stimulated. One Rho family GTPase that is particularly relevant for cancer is RhoC, which has been shown to be up-regulated in a number of metastatic cell lines. How increased RhoC activity promotes invasion and metastasis has not been resolved and is a question that we are pursuing.
One model system that we are studying is leukocyte trans-endothelial migration or extravasation. During inflammation, leukocytes are stimulated to leave the blood stream and enter tissues. This involves leukocyte adhesion to endothelial cells and then migration between endothelial cell junctions, a process that involves a bi-directional signaling between leukocytes and endothelial cells. Because Rho proteins regulate adhesion events and cell migration, we are exploring their role in this process in both cell types, using an in vitro model system. Understanding how leukocytes migrate across an endothelial monolayer is relevant to cancer not only because leukocyte recruitment to tumors is important in the host response to tumors, but also because many tumors metastasize by similar trans-endothelial migration into and out of blood vessels. We have begun to investigate trans-endothelial migration by tumor cells.
Awards and Honors
We demonstrated that upon integrin engagement, RhoA activity is depressed due to the tyrosine phosphorylation of p190RhoGAP. Upon cadherin-mediated adhesion, we have shown that RhoA activity is dramatically suppressed, whereas Rac and Cdc42 activities are stimulated. We have identified an interaction between vinculin and the Arp2/3 complex, involved in nucleating actin filament polymerization. We have provided evidence that this is involved in coupling protrusive activity at the leading edge of cells to sites of new cell adhesion to the matrix.
In collaboration with Channing Der’s lab and with Steen Hansen at Harvard Med School, we have found that RhoE and other members of the Rnd subfamily of Rho proteins inactivate RhoA by activating p190RhoGAP.
- Co-organizer with Rudy Juliano of Keystone Symposium “Signaling via Cell-Cell Interactions,” Keystone, CO. March, 2003
- Appointed Kenan Professor of Cell and Developmental Biology (2003)
- Hyman L. Battle Distinguished Excellence in Teaching Award in the Medical School basic sciences (2003)