Albert Reynolds, Ph.D., left, and graduate student Gregg Wildenberg
have identified broad new roles for p120, a protein Reynolds discovered, in cell behavior and metastasis.
Photo by Pam Martin
Molecular ties that bind provide cancer clues
Researchers at Vanderbilt University Medical Center have identified a molecular mechanism at the hub of numerous cell behaviors — and possibly at the root of metastasis.
In the Dec. 1 issue of the journal Cell, Albert Reynolds, Ph.D., and colleagues identify a protein at the center of it all, p120-catenin, and describe the mechanism it uses to coordinate cell growth, motility and adhesion.
Cells of multicellular organisms have many jobs. They grow, divide and mature into specific cell types.
They slither around, searching for their appropriate place in the body. They also stick tightly together to form tissues.
Although these cell behaviors are inextricably linked, distinct signaling pathways and proteins control the different processes: for example, receptor tyrosine kinases (RTKs) are associated with growth; integrins moderate motility; and cadherins control cell-cell adhesion.
“Historically, these aspects of cellular growth, motility and adhesion have been studied individually because certain receptors are more predominantly involved in growth while others are more important in motility” said Gregg Wildenberg, graduate student in Reynolds' lab and lead author of the study.
“But this paper highlights the concept that all of these systems are mechanistically linked. You can't really think of one without thinking about the other.”
One mechanism that links these systems depends, in part, on a protein called p120-catenin. Reynolds first discovered p120 in 1989 and found that the protein is a key regulator of cadherin function and plays a critical role in cell-cell adhesion. The new study suggests that p120's role in the cell is much broader than previously thought.
“Gregg has figured out that p120 is central, not only to cadherin signaling, but to crosstalk between different systems in the cell that regulate motility, cell-cell adhesion and growth,” said Reynolds.
The research team examined how blocking p120 action affects cultured mouse fibroblasts, a cell type that produces the proteins that make up the extracellular matrix and gives rise to connective tissue.
Surprisingly, they found that RTKs, integrins and cadherins all seem to signal through the cadherin complex and need p120 for key events involving reorganization of the actin cytoskelton, the “molecular scaffolding” of the cell.
These divergent pathways are signaling through another set of proteins, called Rac and Rho, explained Reynolds.
Rac and Rho have been described as molecular “switches” that control multiple aspects of actin reorganization and cell growth. Signaling through RTKs, integrins or cadherins can activate Rac, which in turn cause inhibition of Rho. This antagonism between Rac and Rho regulates the formation and destruction of the actin cytoskeleton that underlies cell shape and motility.
“In many cell types, Rac and Rho are hardwired to one another via a known signaling pathway,” said Reynolds. “We've found that p120 is right in the middle; you can't get from Rac to Rho without p120.”
This observation redefines p120 as a “nexus” of cross-talk between signaling pathways and could help explain how loss of cadherin function causes cancer cells to become metastatic — capable of dislodging from surrounding cells and moving to a new site in the body.
“Clearly, that 'Rac to Rho' inhibition, is very important” said Wildenberg. Blocking p120 activity and disrupting 'Rac to Rho' signaling induced a number of changes in the cells that are typically associated with metastasis, they found.
The current study continues to build the case that p120 participates in processes that govern whether a cancer cell becomes metastatic, and provides a mechanistic link between the behaviors that are disrupted in metastatic cells — something that has been suspected since p120's discovery.
Drugs that target p120, or other components of this complex pathway, could be useful inhibitors of metastasis. In fact, said Reynolds, “everything about the cadherin complex has been implicated in cancer.”
Other authors on the study include: Michael R. Dohn, Robert H. Carnahan, Michael A. Davis, Nichole A. Lobdell, and Jeffrey Settleman.
The research was supported by grants from the National Institutes of Health.