Signaling in control of cell growth and metabolism.

Mammalian cells require growth-factor-receptor-initiated signaling to proliferate. Signal transduction not only initiates entry into the cell cycle, but also reprograms cellular metabolism. This instructional metabolic reprogramming is critical if the cell is to fulfill the anabolic and energetic requirements that accompany cell growth and division. Growth factor signaling mediated by the PI3K/Akt pathway plays a major role in regulating the cellular uptake of glucose, as well as the incorporation of this glucose carbon into lipids for membrane synthesis. Tyrosine-kinase-based regulation of key glycolytic enzymes such as pyruvate kinase also plays a critical role directing glucose carbon into anabolic pathways. In addition, the Myc transcription factor and mTOR kinase regulate the uptake and utilization of amino acids for protein and nucleic acid synthesis, as well as for the supply of intermediates to the mitochondrial Krebs cycle. However, the relationship between cellular signaling and metabolism is not unidirectional. Cells, by sensing levels of intracellular metabolites and the status of key metabolic pathways, can exert feedback control on signal transduction networks through multiple types of metabolite-derived protein modifications. These mechanisms allow cells to coordinate growth and division with their metabolic activity.