A nexus for cellular homeostasis: the interplay between metabolic and signal transduction pathways

Abstract

In multicellular organisms, individual cells have evolved to sense external and internal cues in order to maintain cellular homeostasis and survive under different environmental conditions. Cells efficiently adjust their metabolism to reflect the abundance of nutrients, energy and growth factors. The ability to rewire cellular metabolism between anabolic and catabolic processes is crucial for cells to thrive. Thus, cells have developed, through evolution, metabolic networks that are highly plastic and tightly regulated to meet the requirements necessary to maintain cellular homeostasis. The plasticity of these cellular systems is tightly regulated by complex signaling networks that integrate the intracellular and extracellular information. The coordination of signal transduction and metabolic pathways is essential in maintaining a healthy and rapidly responsive cellular state.

Fig. 1. Anabolic rewiring induced by PI3K/Akt, Ras/ERK and mTORC1 signaling

Extracellular signals activate two major signaling cascades controlled by the activation of PI3K and Ras. PI3K and Ras regulate Akt and ERK, which in turn induce changes in intermediate metabolism to promote anabolic processes. In addition, they also induce the activation of mTORC1, thus further supporting the rewiring of cellular metabolism towards anabolic processes. Through various mechanisms Akt, ERK and mTORC1 stimulate mRNA translation, aerobic glycolysis, glutamine anaplerosis, lipid synthesis, the pentose phosphate and pyrimidine synthesis, thus producing the major components necessary for cell growth and proliferation.

Fig. 2. Regulation of intermediate metabolism by nutrient and energy sensors

Nutrient and energy-responsive pathways fine-tune the output of signaling cascades, allowing for the correct balance between the availability of nutrients and the cellular capacity to use them effectively. AMPK and SIRT1 respond to the energy status of the cells through sensing of AMP and NAD⁺ levels respectively. When energy is scarce these sensors are activated inducing a rewiring of intermediate metabolism to catabolic processes in order to produce energy and restore homeostasis. When nutrients (such as glucose and amino acids) and energy are available, AMPK, SIRT1, SIRT3 and SIRT6 are repressed and mTORC1 is active, thus promoting a shift towards anabolic processes and energy production. These networks of signaling cascades, their interconnection and regulation allow the cells to maintain energetic balance and allow for the physiological adaptation to the ever-changing environment.