Mechanisms and physiopathology of receptor- and ß-arrestin-controlled chemotaxis – arrest&chemotax

Chemotaxis is an important physiological property of many cell types, consisting of the ability to move in the direction of gradients of external signaling molecules. This process regulates the coordinated cell movements that produce morphogenesis during development, participates in tissue wound healing processes and controls the migration of immune cells to sites of infection. In addition, in a pathological context, chemotaxis guides the spread of cancer cells towards attracting factors, determining the development of metastasis within the tissues that release such factors. Oriented cell movement requires two categories of intracellular events, the establishment of a cellular compass and the activation of mechanical forces. Studies of the molecular mechanisms involved in chemotaxis by several groups over the past decade have identified several paradigms and a number of potential molecular players. In our laboratory we have been investigating chemokine receptor cell trafficking, signaling and regulation. A particular effort has been accomplished in the study of ß-arrestins, 2 ubiquitous homologous scaffolding proteins, which are involved in numerous signaling pathways. Based on studies in the literature and recent work in our laboratory, it has emerged that ß-arrestins are key regulators of chemotaxis with multiple impacts in both the establishment of the intracellular compass and in the activation of cellular motility. The general objective of the present proposal is to investigate the physiopathological role of ß-arrestins in receptor-regulated chemotaxis, using a multidisciplinary approach, which associates biochemistry and cell biology, including cellular imaging techniques.