Living with lethal PIP3 levels: viability of flies lacking PTEN restored by a PH domain mutation in Akt/PKB.
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.
Stocker
Hugo
H
Zoologisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Andjelkovic
Mirjana
M
Oldham
Sean
S
Laffargue
Muriel
M
Wymann
Matthias P
MP
Hemmings
Brian A
BA
Hafen
Ernst
E
D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology*; D005123:Eye / Q000254:growth & development; D005260:Female; D017344:Genes, Insect; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008297:Male; D009154:Mutation; D051059:PTEN Phosphohydrolase; D010641:Phenotype; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000502:physiology*; D017956:Photoreceptor Cells, Invertebrate / Q000254:growth & development; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology*; D014638:Vanadates / Q000494:pharmacology
D029721:Drosophila Proteins; D007328:Insulin; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; C076715:pervanadate; C060974:phosphatidylinositol 3,4,5-triphosphate; D014638:Vanadates; C494918:AKT1 protein, human; C494917:Akt1 protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human