title: Nitrogen regulates AMPK to control TORC1 signaling.
abstract: BACKGROUND
  Cell growth and cell-cycle progression are tightly coordinated to enable cells to adjust their size (timing of division) to the demands of proliferation in varying nutritional environments. In fission yeast, nitrogen stress results in sustained proliferation at a reduced size.
  
  
  RESULTS
  Here, we show that cells can sense nitrogen stress to reduce target of rapamycin complex-1 (TORC1) activity. Nitrogen-stress-induced TORC1 inhibition differs from amino-acid-dependent control of TORC1 and requires the Ssp2 (AMPKα) kinase, the Tsc1/2 complex, and Rhb1 GTPase. Importantly, the β and γ regulatory subunits of AMPK are not required to control cell division in response to nitrogen stress, providing evidence for a nitrogen-sensing mechanism that is independent of changes in intracellular ATP/AMP levels. The CaMKK homolog Ssp1 is constitutively required for phosphorylation of the AMPKα(Ssp2) T loop. However, we find that a second homolog CaMKK(Ppk34) is specifically required to stimulate AMPKα(Ssp2) activation in response to nitrogen stress. Finally, ammonia also controls mTORC1 activity in human cells; mTORC1 is activated upon the addition of ammonium to glutamine-starved Hep3B cancer cells.
  
  
  CONCLUSIONS
  The alternative nitrogen source ammonia can simulate TORC1 activity to support growth and division under challenging nutrient settings, a situation often seen in cancer.
authors: Faculty of Life Sciences, University of Manchester, C.4255 Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
authors: Elizabeth
authors: E
authors: Davie
authors: Faculty of Life Sciences, University of Manchester, C.4255 Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
authors: Gabriella M A
authors: GM
authors: Forte
authors: Faculty of Life Sciences, University of Manchester, C.4255 Michael Smith Building, Oxford Road, Manchester M13 9PT, UK; Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, SA 5001, Australia. Electronic address: janni.petersen@flinders.edu.au.
authors: Janni
authors: J
authors: Petersen
mesh_terms: D002455:Cell Division; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D009584:Nitrogen / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012568:Schizosaccharomyces / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D029702:Schizosaccharomyces pombe Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; C573920:Ssp2 protein, S pombe; D058570:TOR Serine-Threonine Kinases; D009584:Nitrogen
references: Mol Cell Biol. 2010 Aug;30(15):3749-57
references: 20516213
references: EMBO J. 2003 Jun 16;22(12):3073-83
references: 12805221
references: Genes Cells. 2012 Aug;17(8):698-708
references: 22762302
references: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3514-9
references: 17360675
references: Cell Cycle. 2010 Oct 1;9(19):3921-32
references: 20935507
references: Hum Mol Genet. 2005 Oct 1;14(19):2851-8
references: 16115814
references: J Cell Sci. 2006 Nov 1;119(Pt 21):4475-85
references: 17046992
references: Genetics. 2000 Jun;155(2):611-22
references: 10835385
references: Curr Biol. 2005 Apr 26;15(8):702-13
references: 15854902
references: Exp Cell Res. 1977 Jul;107(2):377-86
references: 872891
references: J Cell Sci. 2014 Mar 15;127(Pt 6):1346-56
references: 24424027
references: Philos Trans R Soc Lond B Biol Sci. 2011 Dec 27;366(1584):3508-20
references: 22084378
references: PLoS Genet. 2011 Aug;7(8):e1002229
references: 21852960
references: Mol Microbiol. 2005 Nov;58(4):1074-86
references: 16262791
references: J Cell Sci. 2009 Jun 1;122(Pt 11):1737-46
references: 19417002
references: Curr Opin Cell Biol. 2012 Dec;24(6):838-44
references: 22947494
references: Mol Cell. 2008 Apr 25;30(2):214-26
references: 18439900
references: EMBO J. 1995 Feb 1;14(3):492-502
references: 7859738
references: Cell. 2003 Nov 26;115(5):577-90
references: 14651849
references: Nat Cell Biol. 2007 Nov;9(11):1263-72
references: 17952063
references: J Cell Sci. 2012 Apr 15;125(Pt 8):1920-8
references: 22344254
references: Genetics. 2002 Jul;161(3):1053-63
references: 12136010
references: Genes Cells. 2003 Jan;8(1):65-79
references: 12558800
references: Biol Open. 2012 Sep 15;1(9):884-8
references: 23213482
references: Nat Cell Biol. 2004 Nov;6(11):1122-8
references: 15467718
references: Nat Rev Mol Cell Biol. 2012 Apr;13(4):251-62
references: 22436748
references: Mol Cell Biol. 2007 Apr;27(8):3154-64
references: 17261596
references: Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14866-70
references: 10611304
references: Mol Cell. 2003 Jun;11(6):1457-66
references: 12820960
references: Nature. 2005 May 26;435(7041):507-12
references: 15917811
references: Genes Dev. 2013 Oct 1;27(19):2065-71
references: 24115766
references: Trends Cell Biol. 2014 Jul;24(7):400-6
references: 24698685
references: Cell. 2006 Feb 10;124(3):471-84
references: 16469695
references: Cancer Cell. 2007 Jul;12(1):9-22
references: 17613433
references: Mol Cell. 2002 Sep;10(3):457-68
references: 12408816
references: Cell Cycle. 2008 Feb 1;7(3):358-64
references: 18235227
references: Curr Biol. 2014 Feb 17;24(4):428-33
references: 24508166
references: Genes Cells. 2006 Dec;11(12):1367-79
references: 17121544
references: Genes Dev. 2003 Aug 1;17(15):1829-34
references: 12869586
references: EMBO J. 1995 Jul 17;14(14):3325-38
references: 7628434
references: Genes Dev. 1991 Nov;5(11):1990-9
references: 1657709
references: Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1647-55
references: 17284572
references: Trends Endocrinol Metab. 2011 Mar;22(3):94-102
references: 21269838
references: FEBS Lett. 1995 Dec 27;377(3):421-5
references: 8549768
references: Eukaryot Cell. 2012 Feb;11(2):159-67
references: 22140232
references: J Biol Chem. 2002 Jul 5;277(27):23977-80
references: 11997383
references: Curr Top Microbiol Immunol. 2004;279:85-95
references: 14560953
references: J Biol Chem. 1996 Nov 1;271(44):27879-87
references: 8910387
references: J Cell Sci. 2012 Jun 1;125(Pt 11):2655-64
references: 22375066
references: Am J Physiol. 1999 Oct;277(4 Pt 2):F493-7
references: 10516271
references: J Biol Chem. 1999 Nov 26;274(48):34493-8
references: 10567431