PKA (red) activates a PP1 inhibitor (green) to steer growth cones.

Like a pack of teenagers, the sundry proteins that steer a growth cone stick close together, Han et al. show on page 101.

Growth cones are the trailblazers at the tip of growing axons. Their paths are lit by a combination of attractive and repulsive cues in the extracellular matrix. Attraction, via growth cone turning toward a cue, is linked to high axonal levels of cAMP, but its collaborators in the process are unknown.

The authors have now identified the downstream effectors of cAMP during attraction by examining one of its favorite targets: protein kinase A (PKA). They found that the type II form of PKA is strongly enriched in growth cone filopodia. PKA activity and its filopodial localization—mediated by a member of the AKAP adaptor protein family—were required for cAMP-induced attraction.

In growth cone filopodia, PKA was found in a complex containing the PP1 phosphatase and its inhibitor, I-1. The authors show that, during cAMP-induced growth cone turning, PKA activates I-1 and thereby inhibits PP1. In the absence of I-1, attraction was blocked.

In other contexts, one of PP1's known targets is CaMKII, whose activation on one side of a growth cone is known to create turning in that direction, probably by increasing actin dynamics. PKA's inhibition of PP1 should also tip the scales in CaMKII's favor.

The colocalization of PKA with its downstream targets has also been seen in cardiac muscle cells. PKA is a promiscuous enzyme, so the strict positioning of PKA in signaling complexes that are tethered in place is probably necessary to ensure only localized responses.