Kinetic Modeling and Analysis of the Akt/Mechanistic Target of Rapamycin Complex 1 (mTORC1) Signaling Axis Reveals Cooperative, Feedforward Regulation

Mechanistic target of rapamycin complex 1)mTORC1) controls biosynthesis and has been implicated in uncontrolled cell growth in cancer. Although many details of mTORC1 regulation are well understood, a systems- level, predictive framework synthesizing those details is currently lacking. We constructed various mathematical models of mTORC1 activation mediated by Akt and aligned the model outputs to kinetic data acquired for growth factor- stimulated cells. A model based on a putative feedforward loop orchestrated by Akt consistently predicted how the pathway was altered by depletion of key regulatory proteins. Analysis of the successful model also elucidates two dynamical motifs: neutralization of a negative regulator, which characterizes how Akt indirectly activates mTORC1, and seesaw enzyme regulation, which describes how activated and inhibited states of mTORC1 are controlled in concert to produce a nonlinear, ultrasensitive response. Such insights lend quantitative understanding of signaling networks and their precise manipulation in various contexts.