Akt (green) and APPL1(red) colocalize (arrows) on endosomes, where APPL1 triggers Akt signaling.

ZERIAL/ELSEVIER

For Akt signaling, location matters, according to Annette Schenck, Marino Zerial (Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany), and colleagues.

Akt (protein kinase B) influences a wide variety of pathways in the cell, but how it divides its activity between them was unclear. Akt is known to signal from the plasma membrane, but an upstream regulator of Akt called APPL1, which is known to interact directly with Akt, has been reported to reside on endosomes.

Here, the authors showed that loss of APPL1 affected the activity of some downstream targets of Akt, but not others. For example, the activity of Gsk-3β, an Akt target involved in cell survival, was diminished by APPL1 loss, while the activity of Tsc2, an Akt target that promotes growth, was unaffected.

These differential effects were tied to differences in location: Gsk-3β, but not Tsc2, linked up with Akt and APPL1 on the endosome. And the endosomal location was clearly important, since neither nuclear-targeted nor cytosolic APPL1 could rescue cells with depleted endosomal APPL1.

“This is the first time Akt signaling has been shown from the endosome,” Zerial says. “We think these results should make the signaling community take seriously the contribution of endocytic trafficking to the quality and quantity of signaling.”

Schenck, A., et al.
2008
.
Cell.
133
:
486
–497.