Mechanisms of Cell Motility and Adhesion
|Figure 1. Palladin (in green) is concentrated in closely-spaced spots associated with contractile bundles of actin filaments (in red), in a cultured A7r5 vascular smooth muscle cell.|
Many physiology processes depend upon the regulated movement of cells. Examples include embryological morphogenesis, wound healing and targeting of immune cells to sites of infection. However, when cell motility goes awry, this can result in serious pathologies. The inappropriate movement of cancer cells during metastasis is one example; the movement of cells into the lumen of an artery during restenosis is another. My lab studies the molecular basis of normal, regulated cell motility to understand how this fundamental process is controlled and how it is subverted to give rise to pathological situations. We have focused on the actin cytoskeleton, which is largely responsible for establishing the shape of the cell and for controlling the changes in shape that occur when a cell crawls. It is thought that rapid polymerization of actin at the cell’s leading edge is responsible for pushing the front of the cell forward, while actin microfilaments in the body of the cell simultaneously undergo contraction in order to pull the rest of the cell up. Our goal is to identify the molecular mechanisms that regulate both the protrusive assembly and the contractility of actin filaments.
Currently, we are focusing much attention on a novel protein that was discovered in the Otey lab and named palladin. Palladin has many features suggesting that it plays a critical role in regulating actin dynamics. First, it closely co-localizes with actin-rich structures in a variety of cell types. Second, it binds to a large number of proteins that are known to control actin assembly. Third, its presence is required in order for a cell to maintain its actin cytoskeleton: when palladin expression is inhibited in a cultured cell, that cell’s cytoskeleton completely disassembles. Conversely, when palladin is overexpressed in a cultured cell, this stimulates the formation of super-robust actin arrays.
Projects in the lab utilize a combination of biochemistry and molecular biology to explore palladin function in both cultured cell and animal models, using palladin as a unique tool to learn about mechanisms of cell motility. Currently, we and our collaborators are exploring palladin’s role in cancer metastasis. Microarray results from multiple labs have shown that palladin is part of the “molecular signature of cell invasion”, suggesting that palladin may be upregulated specifically in the metastatic sub-population of cancer cells. We are working with human tumor-derived cell lines and samples from cancer patients to understand palladin’s role in invasive cancers, including breast cancer.
Recently, the Otey lab participated in a multi-lab collaborative effort that implicated palladin in pancreatic adenocarcinoma, which is an unusually deadly cancer. This study was focused on a large family with an exceptionally high incidence of familial pancreatic cancer. In this kindred, a point mutation in the palladin gene was found in the affected members of the family, and not in the unaffected members, suggesting that palladin mis-regulation might have a critical role in promoting tumor formation. Current efforts are focused on understand the role of palladin in both inherited and non-inherited (sporadic) forms of pancreatic cancer, with the goal of using this information to improve methods for early diagnosis of the disease.