Project 451560

Movement of cells as a group plays an important role in development of an embryo and is also key for tissue regeneration following injury. Further, this process also helps cancer cells to spread to distant organs. This unique type of cell movement is characterized by high level of coordination between cells, that maintain contact with each other. On the other hand, the moving group's edge is free of contacts and generates very dynamic protrusions, crucial for movement. The cell contacts are important regulators of this process, however details of how they contribute are not yet known. We will explore the role of a protein located at the cell contact sites, claudin-3. This protein is abundant in various tumors (e.g. prostate, ovarium, intestinal cancers), and was implicated in spreading of these cancers. It also has crucial roles in the kidney. We found that experimental deletion of this protein from cells reduced their ability to move and generate protrusions. We also identified a potential binding partner for this protein, called TNIK. Based on these, we propose that claudin-3 helps migration by coordinating events needed for front protrusions and by strengthening group coherence. Further, we think that part of the effects of claudin-3 can be attributed to TNIK. To test these theories, we will use cultured tubular and cancer cells. We will manipulate the abundance, location and interactions of claudin-3 and use microscopy techniques to explore how this affects various aspects of group migration. Taken together, we will define the cellular and molecular modes whereby claudin-3 controls cell migration and assess the specific role of the claudin-3-TNIK interaction. Our studies will help understand molecular events during group migration and define how claudin-3 is linked to these. This knowledge is vital to understand cancer spreading and tissue regeneration. Thus, our studies may lead to new interventions to influence these important processes.