Re-evaluating AKT regulation: role of TOR complex 2 in tissue growth.
Phosphatidylinositol-3-kinase (PI3K)/AKT signaling is essential for growth and metabolism and is elevated in many cancers. Enzymatic activity of AKT has been shown to depend on phosphorylation of two conserved sites by PDK1 and TOR (target of rapamycin) complex 2 (TORC2) in a PI3K-dependent manner. Here we analyze the role of TORC2-mediated AKT phosphorylation in Drosophila. Mutants removing critical TORC2 components, rictor and sin1, strongly reduced AKT hydrophobic motif (HM) phosphorylation and AKT activity, but showed only minor growth impairment. A mutant form of AKT lacking the HM phosphorylation site displayed comparable activity. In contrast to the mild effects of removing HM site phosphorylation at normal levels of PI3K activity, loss of TORC2 activity strongly inhibited hyperplasia caused by elevated pathway activity, as in mutants of the tumor suppressor PTEN. Thus, TORC2 acts as a rheostat to broaden the range of AKT signaling at the high end of its range.
Hietakangas
Ville
V
European Molecular Biology Laboratory Meyerhofstrasse 1, D-69117 Heidelberg, Germany.
Cohen
Stephen M
SM
D000595:Amino Acid Sequence; D000818:Animals; D004330:Drosophila / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017344:Genes, Insect; D008969:Molecular Sequence Data; D009154:Mutation; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
D029721:Drosophila Proteins; D015534:Trans-Activators; D051057:Proto-Oncogene Proteins c-akt