Here's a pretty cool breakthrough in Alt signaling published in Cell this week. Makes sense if you think about it. So what do the Akt folks make of this?


The Endosomal Protein Appl1 Mediates Akt Substrate Specificity and Cell Survival in Vertebrate Development

Annette Schenck1, 4, Livia Goto-Silva1, Claudio Collinet1, Muriel Rhinn2, 5, Angelika Giner1, Bianca Habermann1, 3, Michael Brand2 and Marino Zerial1, ,


Cell Volume 133, Issue 3, 2 May 2008, Pages 486-497

Abstract from Cell
During development of multicellular organisms, cells respond to extracellular cues through nonlinear signal transduction cascades whose principal components have been identified. Nevertheless, the molecular mechanisms underlying specificity of cellular responses remain poorly understood. Spatial distribution of signaling proteins may contribute to signaling specificity. Here, we tested this hypothesis by investigating the role of the Rab5 effector Appl1, an endosomal protein that interacts with transmembrane receptors and Akt. We show that in zebrafish, Appl1 regulates Akt activity and substrate specificity, controlling GSK-3ß but not TSC2. Consistent with this pattern, Appl1 is selectively required for cell survival, most critically in highly expressing tissues. Remarkably, Appl1 function requires its endosomal localization. Indeed, Akt and GSK-3ß, but not TSC2, dynamically associate with Appl1 endosomes upon growth factor stimulation. We propose that partitioning of Akt and selected effectors onto endosomal compartments represents a key mechanism contributing to the specificity of signal transduction in vertebrate development.