Chemotaxis is a fascinating biological response in which cells orient themselves and move up a chemical gradient. It is important in a variety of physiological and pathological processes including nerve growth, angiogenesis, wound healing, leukocyte trafficking, and carcinoma invasion. It is also essential for the survival of the social amoebae, Dictyostelium discoideum. During growth, these cells track down and phagocytose bacteria. When starved, they enter a differentiation program that allows the cells to survive harsh environmental conditions. They do so by chemotaxing toward secreted adenosine 3,5 cyclic monophosphate (cAMP) signals thereby forming aggregates which differentiate into spore and stalk cells. The essential role of chemotaxis in this eukaryote has provided an excellent model organism to study the biochemical and genetic basis of directed cell migration. Much like their mammalian counterparts, Dictyostelium cells use G protein-linked signaling pathways to respond to chemoattractants. Binding of chemoattractants to serpentine receptors leads to the dissociation of heterotrimeric G proteins into alpha- and beta/gamma-subunits, which activate a variety of effectors that go on to produce multiple responses. These include increases in Ca2+ influx, IP3, cAMP and cGMP. Concomitantly, the level of phosphorylation of myosins I and II and polymerized actin are markedly increased. Our research program is focused on understanding how these multiple G protein-coupled signaling events are translated into directed cell migration. We have shown that a variety of signaling events are spatially restricted during chemotaxis. In one instance, this has led us to discover a novel and unexpected mechanism used by Dictyostelium cells to relay and amplify chemotactic gradients. It has been observed that these cells align in a head to tail fashion, or stream, as they migrate in a gradient of cAMP. We have shown that the adenylyl cyclase ACA, which converts ATP into cAMP, is distributed in two distinct pools in polarized cells;one is restricted to the plasma membrane, and the other is localized on highly dynamic intracellular vesicles. These vesicles coalesce at the back of cells through mechanisms that depend on the actin and microtubule cytoskeleton, and require de novo protein synthesis. Further studies allowed us to propose that the asymmetric distribution of ACA provides a compartment from which cAMP is secreted to locally attract neighboring cells, thereby providing a unique mechanism to amplify chemical gradients. In the past few years, we have witnessed impressive progress in our understanding of how chemotactic signals transduce spatial and temporal information to the cytoskeletal machinery. Yet, many fundamental questions remain unanswered. In particular, the mechanisms by which signals are integrated at the cellular and multi-cellular levels are essentially unknown. In the years ahead, we will continue exploring two fundamental questions in chemotaxis: 1. How external signals establish and maintain signaling and cellular polarity? 2. How are chemotactic signals relayed to neighboring cells, i.e. how do cells transition from single to group migration?

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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McCann, Colin P; Rericha, Erin C; Wang, Chenlu et al. (2014) Dictyostelium cells migrate similarly on surfaces of varying chemical composition. PLoS One 9:e87981
Majumdar, Ritankar; Sixt, Michael; Parent, Carole A (2014) New paradigms in the establishment and maintenance of gradients during directed cell migration. Curr Opin Cell Biol 30:33-40
Brzostowski, Joseph A; Sawai, Satoshi; Rozov, Orr et al. (2013) Phosphorylation of chemoattractant receptors regulates chemotaxis, actin re-organization, and signal-relay. J Cell Sci :