D. discoideum amobae chemotax towards a gradient source. As they migrate, D. discoideum line up in a head-to-tail fashion to form aggregates. Imaging ACA–YFP reveals plasma membrane labelling that is highly enriched at the uropod of polarized cells. Image provided by C. Parent.

The ability of cells to polarize and migrate up a chemical gradient is key to a variety of processes, from axon guidance to leukocyte homing. This ability to chemotax is also key to the survival of the social amoebae Dictyostelium discoideum during times of starvation, and studies in this system have provided important insights into the molecular mechanisms directing chemotaxis. One key question in the field is how migrating cells amplify chemo-attractant gradients, and new work published by Kriebel et al. (Cell 112, 549–560 (2003)) now provides a model for this. They show that D. discoideum cells amplify the gradient of the chemo-attractant cyclic AMP by asymmetrically localizing the enzyme responsible for its generation.

On exposure to a cAMP chemo-attractant gradient, D. discoideum cells polarize, begin to migrate towards the gradient source, and then line up head-to-tail in streams to form aggregates that are key to their survival. Now, Kriebel et al. propose that by localizing adenylyl cyclase (ACA) — the enzyme responsible for generating cAMP — to the uropod during polarization, migrating cells can then themselves produce cAMP from their tail. In this way, they provide an amplified cAMP signal for the cells behind to follow.

Cells lacking ACA can polarize when exposed to a chemo-attractant gradient, but cannot then line up to form streams. To see where ACA localizes in the cell, the authors fused ACA to yellow fluorescent protein (YFP) and found that after polarization, ACA is highly enriched at the uropod. Intriguingly, ACA is also present in intracellular vesicles, suggesting that vesicular transport may be involved in its localization or in the signal transduction pathways that result in its activation.

So what is the pathway that mediates ACA localization? Neither CRAC (cytosolic regulator of adenylyl cyclase), which activates ACA, nor PKA (protein kinase A), a target of ACA, seem to be involved. By perturbing the actin cytoskeleton with drug treatments, the authors find that the actin cytoskeleton is important for ACA localization, but the exact mechanism by which this takes place remains to be established. The enzymatic activity of ACA also affects its localization, as cells expressing a constitutively active mutant of ACA are also unable to stream.

The importance of this work is that it suggests an amplifying mechanism by which migrating cells responding to a chemo-attractant can then themselves become a source of chemo-attractant for other cells to follow. This signal relay may also be common to other mammalian cell types. In leukocytes, for example, it is known that migrating cells secrete chemo-attractant in response to chemo-attractant exposure. This work, therefore, may provide a basis for future studies into the relay mechanisms used by diverse chemotactic cell types.