Systematic Identification of TOR Downstream Effectors Using Random-Walks on
the Yeast Interactome

Shahin Mohammadi, Shankar Subramaniam, and Ananth Grama
Center for Science of Information.


Calorie restriction (CR), without malnutrition, is one of the most conserved non-genetic
interventions that extends both the mean, and the maximum life-span in evolutionarily
distant species, ranging from yeast to mammals. The target of rapamycin (TOR) has been
shown to play a key role in mediating life-span extension in response to the CR,
by modulating cellular response to nutrient-availability and orchestrating various
components of cellular machinery, including cell growth, translation initiation,
ribosome biogenesis, and autophagy. Furthermore, both genetic and pharmacological
interventions inhibiting the TOR pathway exhibit a similar phenotype, which can not
be further extended by CR. These observations have motivated experimental investigations
of downstream effectors of TOR, which are responsible for mediating life-span extension.

In this talk, we present the first comprehensive computational map of downstream
effectors of TOR. We adopt a systematic approach, based on the known random-walk
method for tracing information flow in the yeast interactome. Using a rigorous
statistical framework, we identify targets carrying significant amounts of
TOR signaling. Our approach, unlike experimental methods, is not limited to specific
aspects of cellular response. Rather, it is shown to predict transcriptional changes,
as well as post-translational modifications in response to TOR signaling. GO
enrichment analysis of the identified effectors not only sheds light on the
functional mechanisms downstream of TOR, but also provides mechanistic understanding
of the crosstalk among them. In addition to identifying several known effectors,
our method also identifies a number of other targets, whose roles have been
hypothesized in literature but not confirmed; as well as potential new targets.

