My laboratory studies how planar cell polarity is regulated during complex migration events such as the collective movement of embryonic zebrafish gastrula cells. We use a combination of in vivo methodologies in the zebrafish embryo and in vitro techniques in human cancer cells to identify underlying molecular mechanisms. We are particularly interested in understanding how components of the planar cell polarity (PCP) pathway interact with other regulators of cell migration including matrix metalloproteinases, integrins, and fibronectin. It has become clear that the collective movement of polarized cells (during embryogenesis and cancer) requires coordinated regulation of integrin-extracellular matrix (ECM) interactions, proteolytic ECM remodeling, and cell-cell adhesion. Here, integrins function as transmembrane receptors for ECM proteins such as fibronectin while membrane type-1 matrix metalloproteinase (Mmp14) cleaves ECM. Mmp14 is activated intracellularly therefore endocytic and recycling pathways tightly regulate its expression at the cell surface. Rapid remodeling of cadherin-mediated cell adhesion allows dynamic changes in cell coupling while maintaining coherent movement of cell populations. However, though integrins, Mmp14, and N-cadherin are required for collective movement, their molecular relationship with PCP proteins is unclear. Our studies and preliminary data support a novel model whereby PCP proteins differentially influence integrin/Mmp14 and N-cadherin function, respectively, to regulate membrane protrusive activity and polarity underlying the collective migration of zebrafish gastrula cells. My laboratory's goal is to significantly expand our knowledge of PCP in migrating cells. Our research will also have implications for PCP in other morphogenetic and disease processes. For example, mutations in human Van Gogh genes (encoding a transmembrane PCP protein) occur in patients with defects in neural tube closure, a process driven by convergent extension cell movements. Human cancer cells also express PCP proteins, and we showed that loss of Vangl2 increases tumor cell invasiveness indicating that Vangl2 might function as a metastasis suppressor. Collective migration of polarized cells is considered an effective invasion strategy of mesenchymal and epithelial cancers. Therefore, we contend that studying how PCP signaling coordinates cell-matrix interactions, proteolysis, and cadherin-mediated cell cohesion is directly relevant to our understanding of tumor invasion of host tissues. To address our many research questions, my laboratory takes an integrative approach that utilizes multiple techniques: molecular methods, immunolabeling, western blot, in situ hybridization, mRNA and antisense morpholino microinjection of zebrafish embryos, time-lapse and confocal microscopic imaging, and human cell culture.