PT  - JOURNAL ARTICLE
AU  - Poulami Dutta
AU  - Vimalathithan Devaraj
AU  - Biplab Bose
TI  - A Negative Feedback Regulates The Flow Of Signal Through Akt/mTORC1/S6K1 Pathway
AID  - 10.1101/147710
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 147710
4099  - http://biorxiv.org/content/early/2017/06/08/147710.short
4100  - http://biorxiv.org/content/early/2017/06/08/147710.full
AB  - Several growth factors, cytokines, hormones activate PI3K/Akt pathway. Akt is a key node in this pathway and activates different downstream paths. One such path is Akt/mTORC1/S6K1 that controls protein synthesis, cell survival, and proliferation. Here we show that a negative feedback controls activation of S6K1 through this pathway. Due to this negative feedback, a sustained phospho-Akt signal generates a transient pulse of phospho-S6K1. We have created a mathematical model for this circuit. Analysis of this model shows that the negative feedback acts as a filter and preferentially allows a signal, with sharp and faster rise of phospho-Akt, to induce pronounced activation of S6K1. It blocks an input with a fast oscillation of phospho-Akt to flow through this path. We show that this negative feedback leads to differential activation of S6K1 by Insulin and Insulin-like Growth Factor 1. Such differential effect may explain the difference in the mitogenic effect of these two molecules.