Evolution of the TOR Pathway

Abstract

The TOR kinase is a major regulator of growth in eukaryotes. Many components of the TOR pathway are implicated in cancer and metabolic diseases in humans. Analysis of the evolution of TOR and its pathway may provide fundamental insight into the evolution of growth regulation in eukaryotes and provide a practical framework on which experimental evidence can be compared between species. Here we performed phylogenetic analyses on the components of the TOR pathway and determined their point of invention. We find that the two TOR complexes and a large part of the TOR pathway originated before the Last Eukaryotic Common Ancestor and form a core to which new inputs have been added during animal evolution. In addition, we provide insight into how duplications and sub-functionalization of the S6K, RSK, SGK and PKB kinases shaped the complexity of the TOR pathway. In yeast we identify novel AGC kinases that are orthologous to the S6 kinase. These results demonstrate how a vital signaling pathway can be both highly conserved and flexible in eukaryotes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00239-011-9469-9) contains supplementary material, which is available to authorized users.

Role of AMP-activated protein kinase in metabolic depression in animals

“…AMPK activation in Drosophila cells led to TSC2 phosphorylation at the equivalent of the second site, Ser1338, which is well conserved in insects (Kim and Lee 2015). However, TSC2 is absent in many lower eukaryotes, including S. cerevisiae (van Dam et al 2011). AMPK also phosphorylates the TOR binding partner raptor (Fig.…”

“…A key player in control in mammals is the mammalian target of rapamycin complex 1 (mTORC1). Like AMPK, TOR kinase is an ancient protein kinase (van Dam et al 2011). Activation of mTORC1 leads to activation of p70 ribosomal protein S6 kinase (S6K), which in turn phosphorylates 40S ribosomal protein S6 (rpS6) (Fig.…”

The Opposing Actions of Target of Rapamycin and AMP-Activated Protein Kinase in Cell Growth Control

“…1) (Inoki et al 2006). Although the AMPK sites in TSC2 are conserved in vertebrates, they are not present in D. discoideum or S. pombe (Huang and Manning 2008;Serfontein et al 2011;van Dam et al 2011). Moreover, the TSC complex is absent in S. cerevisiae, C. elegans, and A. thaliana.…”

Polyphenols and the Human Brain: Plant “Secondary Metabolite” Ecologic Roles and Endogenous Signaling Functions Drive Benefits

“…In benign conditions of nutrient and energy availability, TOR upregulates a vast range of energy-consuming activities, such as metabolism, cell proliferation, and the translation of mRNA, ultimately dictating a wealth of developmental and metabolic processes by regulating other key kinases (199,200). The TOR kinase pathways are, again, highly conserved, having originated before the last common eukaryotic ancestor, and both their function and core molecular components, including the upstream PI3K/PKB pathway, are shared across the cells of nearly all eukaryotic clades (201). For instance, in plants, TOR signaling pathways play a large part in regulating growth, with the TOR gene expressed most abundantly in rapidly growing and dividing tissues.…”