Schematic overview of the model.

<p>This diagram depicts the proteins considered in the model and regulatory influences among these proteins, as well as model inputs and outputs. Two inputs are considered: the level of rapamycin in complex with FKBP1A and therefore competent to inhibit MTORC1 (i.e., the level of rapamycin*) and the level of AMPK with activating phosphorylation in its kinase domain (i.e., the level of AMPK*). We note that AMPK activity is limited by the level of AMPK* and also the level of inhibitory phosphorylation of AMPK by ULK1. Thus, AMPK* does not necessarily correspond to the level of active AMPK. AMPK negatively regulates MTORC1 and positively regulates ULK1. A dashed arrow is used to represent the negative influence of AMPK on MTORC1 because this influence is not considered until the “Sensitivity analysis” section. Key regulatory influences considered in the model are mutual inhibition of MTORC1 and ULK1 and (slow) negative feedback from ULK1 to AMPK. Two outputs are considered: the level of phosphorylation of EIF4EBP1, a repressor of translation, and the level of phosphorylation of AMBRA1, which is involved in activating autophagy. We consider phosphorylation of EIF4EBP1 to be indicative of a translation state and phosphorylation of AMBRA1 to be indicative of an autophagy state.