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Molecular Insight into Chemotactic Signaling

Dictyostelium, human leukocytes, as well as other types of cells possess the ability to polarize and move in a directed fashion in response to chemoattractants. In Dictyostleium the most potent chemoattractant is cAMP, which, like chemokines, transduces its effects by binding to G protein‐coupled receptors. The binding of cAMP to its receptor activates a plethora of responses, including the activation of the adenylyl cyclase ACA, which converts ATP to cAMP. ACA activation requires Gβγ‐subunits, the PH‐domain‐containing protein CRAC (Cytosolic Regulator of Adenylyl Cyclase), and the Target Of Rapamycin Complex 2. While part of the cAMP synthesized remains inside the cells to activate downstream effectors, the majority of cAMP is secreted to relay the chemoattractant signal to neighboring cells. We find that ACA is highly enriched at the back of cells and is essential for their ability to migrate in a head‐to‐tail fashion during chemotaxis. The asymmetric distribution of ACA is not dependent on the presence of PKA or CRAC. In addition, ACA remains enriched at the back of cells lacking either PAKa or myosin II, both of which localize at the cell posterior. However, the asymmetric distribution of ACA requires vesicular trafficking and involves intact actin and microtubule networks, as well as de novo protein synthesis. We propose that the asymmetric distribution of ACA provides a compartment from with cAMP is secreted to locally act as a chemoattractant and suggest that similar compartmentalization mechanisms exist in mammalian cells during embryogenesis, wound healing, neuron growth, and metastasis.