title: Kinetic Modeling and Analysis of the Akt/Mechanistic Target of Rapamycin Complex 1 (mTORC1) Signaling Axis Reveals Cooperative, Feedforward Regulation.
abstract: 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.
authors.affiliation: From the Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, 27695-7905.
authors.forename: Anisur
authors.initials: A
authors.lastname: Rahman
authors.affiliation: From the Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, 27695-7905 jason_haugh@ncsu.edu.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Haugh
mesh_terms: D000818:Animals; D007700:Kinetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D041681:NIH 3T3 Cells; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Akt PKB; feedforward loop; mammalian target of rapamycin (mTOR); mathematical modeling; protein kinase; signal transduction