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Living with Lethal PIP3 Levels: Viability of Flies Lacking PTEN Restored by a PH Domain Mutation in Akt/PKB
Hugo Stocker,1Mirjana Andjelkovic,2*Sean Oldham,1Muriel Laffargue,3Matthias P. Wymann,3Brian A. Hemmings,2Ernst 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 downstreameffectors
to deregulated growth and tumorigenesis remain uncertain.We provide
genetic evidence in Drosophila melanogaster for theparamount importance of the protein kinase Akt [also called proteinkinase B (PKB)] in mediating the effects of increased
phosphatidylinositol3,4,5-trisphosphate (PIP3) concentrations that are
caused by theloss of PTEN function. A mutation in the pleckstrin
homology (PH)domain of Akt that reduces its affinity for PIP3 sufficed
to rescuethe lethality of flies devoid of PTEN activity. Thus, Akt
appearsto be the only critical target activated by increased PIP3
concentrationsin 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
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