Growth control via TOR kinase signaling, an intracellular sensor of amino acid and energy availability, with crosstalk potential to proline metabolism.
The TOR (Target of Rapamycin) protein kinase pathway plays a central role in sensing and responding to nutrients, stress, and intracellular energy state. TOR complex 1 (TORC1) is comprised of TOR, Raptor, and Lst8 and its activity is sensitive to inhibition by the macrolide antibiotic rapamycin. TORC1 regulates protein synthesis, ribosome biogenesis, autophagy, and ultimately cell growth through the phosphorylation of S6 K, 4E-BP, and other substrates. As TORC1 activity is positively or negatively modulated in response to upstream regulators, cellular growth rate is, respectively, enhanced or suppressed. A separate multiprotein TOR complex, TORC2, is insensitive to direct inhibition by rapamycin and does not regulate growth patterns directly; TORC2 can, however, impact certain aspects of TORC1 signaling and cell survival. TOR signaling is an ancient pathway, conserved among the yeasts, Dictyostelium, C. elegans, Drosophila, mammals, and Arabidopsis. This review will focus on the regulation of TORC1 in mammalian cells in the context of amino acid sensing/regulation and intracellular ATP homeostasis, but will also include comparisons among other organisms.
Liao
Xin-Hua
XH
Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-8028, USA.
Majithia
Amit
A
Huang
Xiuli
X
Kimmel
Alan R
AR
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D029681:Arabidopsis Proteins; D004023:Dictyostelium / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D011392:Proline / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D020123:Sirolimus / Q000378:metabolism; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D000596:Amino Acids; D029681:Arabidopsis Proteins; D019869:Phosphatidylinositol 3-Kinases; D011392:Proline; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus; D022061:Tacrolimus Binding Protein 1A; D014157:Transcription Factors; C500984:CRTC1 protein, human; C512171:TOR protein, Arabidopsis