Isolation and Analysis of Human Kekkon-Like Molecules, a Family of Potential Inhibitors of ErbB Receptor Tyrosine Kinases
Annual summary rept. 1 Apr 2002-31 Mar 2005
HARVARD MEDICAL SCHOOL BOSTON MA
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Receptor Tyrosine Kinase RTK activation triggers P13 Kinase dependent Akt survival signaling. At the onset of this project, no genes involved in the feedback regulation of the PI3K - Akt signaling branch were known. In order to identify genes involved in the intrinsic negative feedback regulation of the activity of PI3K-Akt in vivo, I used Drosophila as a model system and performed unbiased cell based genome wide screens employing double stranded RNA interference dsRNAi, measuring Akt phosphorylation as a readout for pathway activity. The results indicate that the activity of PI3K-Akt is indeed subject to feedback regulation, which is exerted by the TsclTsc2-Rheb-Tor pathway in a S6K dependent manner. This feedback control is not only present in tissue culture cells, but is also deployed during Drosophiladevelopment and is conserved in mammals, In addition, the data suggests a second regulatory connection between the PI3K and Tor signaling pathways via a dynamic equilibrium between the two distinct Tor containing complexes. Therefore, inhibition of Tor inevitably causes elevated levels of Akt activity. The results warrant caution to rely on the Tor inhibitor rapamycin and its derivatives as a single agent in anti cancer therapy.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology
- Medicine and Medical Research