Living with Lethal PIP3 Levels: Viability of Flies Lacking PTEN Restored by a PH Domain Mutation in Akt/PKB
Hugo Stocker,1
Mirjana Andjelkovic,2*
Sean Oldham,1
Muriel Laffargue,3
Matthias P. Wymann,3
Brian A. Hemmings,2
Ernst Hafen1
The phosphoinositide phosphatase PTEN is mutated in many human
cancers. Although the role of PTEN has been studied extensively, the
relative contributions of its numerous potential downstream effectors
to deregulated growth and tumorigenesis remain uncertain. We provide
genetic evidence in Drosophila melanogaster for the paramount importance of the protein kinase Akt [also called protein kinase B (PKB)] in mediating the effects of increased
phosphatidylinositol 3,4,5-trisphosphate (PIP3) concentrations that are
caused by the loss of PTEN function. A mutation in the pleckstrin
homology (PH) domain of Akt that reduces its affinity for PIP3 sufficed
to rescue the lethality of flies devoid of PTEN activity. Thus, Akt
appears to be the only critical target activated by increased PIP3
concentrations in Drosophila.
1 Zoologisches Institut der Universität
Zürich, Winterthurerstrasse 190, CH-8057 Zürich,
Switzerland.
2 Friedrich Miescher Institute,
Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
3 Université de Fribourg, Rue du Musée
5, CH-1700 Fribourg, Switzerland.
*
Present address: Department of Vascular and Metabolic Diseases,
F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland.
To whom correspondence should be addressed. E-mail:
hafen{at}zool.unizh.ch
