title: Chemoattractant stimulation of TORC2 is regulated by receptor/G protein-targeted inhibitory mechanisms that function upstream and independently of an essential GEF/Ras activation pathway in Dictyostelium.
abstract: Global stimulation of Dictyostelium with different chemoattractants elicits multiple transient signaling responses, including synthesis of cAMP and cGMP, actin polymerization, activation of kinases ERK2, TORC2, and phosphatidylinositide 3-kinase, and Ras-GTP accumulation. Mechanisms that down-regulate these responses are poorly understood. Here we examine transient activation of TORC2 in response to chemically distinct chemoattractants, cAMP and folate, and suggest that TORC2 is regulated by adaptive, desensitizing responses to stimulatory ligands that are independent of downstream, feedback, or feedforward circuits. Cells with acquired insensitivity to either folate or cAMP remain fully responsive to TORC2 activation if stimulated with the other ligand. Thus TORC2 responses to cAMP or folate are not cross-inhibitory. Using a series of signaling mutants, we show that folate and cAMP activate TORC2 through an identical GEF/Ras pathway but separate receptors and G protein couplings. Because the common GEF/Ras pathway also remains fully responsive to one chemoattractant after desensitization to the other, GEF/Ras must act downstream and independent of adaptation to persistent ligand stimulation. When initial chemoattractant concentrations are immediately diluted, cells rapidly regain full responsiveness. We suggest that ligand adaptation functions in upstream inhibitory pathways that involve chemoattractant-specific receptor/G protein complexes and regulate multiple response pathways.
authors: Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-8028, USA.
authors: Xin-Hua
authors: XH
authors: Liao
authors: Jonathan
authors: J
authors: Buggey
authors: Yun Kyung
authors: YK
authors: Lee
authors: Alan R
authors: AR
authors: Kimmel
mesh_terms: D002633:Chemotaxis; D000242:Cyclic AMP / Q000494:pharmacology; D004023:Dictyostelium / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D005492:Folic Acid / Q000494:pharmacology; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D046912:Multiprotein Complexes; D015800:Protozoan Proteins; D043562:Receptors, G-Protein-Coupled; C489016:ras protein, Dictyostelium; C450520:seven-transmembrane G-protein-coupled receptor; D005492:Folic Acid; D000242:Cyclic AMP; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020962:Heterotrimeric GTP-Binding Proteins; D018631:ras Proteins
references: Differentiation. 1986;32(3):192-9
references: 2878851
references: Science. 2001 Mar 23;291(5512):2408-11
references: 11264536
references: J Cell Biol. 1995 Jun;129(6):1659-65
references: 7790361
references: EMBO Rep. 2007 May;8(5):477-82
references: 17380187
references: Genes Dev. 2004 Apr 1;18(7):805-15
references: 15059962
references: Cell. 2009 Aug 21;138(4):760-73
references: 19703401
references: Semin Cell Dev Biol. 1998 Apr;9(2):119-27
references: 9599406
references: J Biol Chem. 1992 Mar 5;267(7):4600-7
references: 1537842
references: Sci Signal. 2012 Jan 03;5(205):ra2
references: 22215733
references: Mol Biol Cell. 1993 Mar;4(3):283-92
references: 8485319
references: Biochem Biophys Res Commun. 1983 Aug 30;115(1):130-6
references: 6311201
references: Mol Biol Cell. 1992 Jul;3(7):735-47
references: 1355376
references: Mol Biol Cell. 2006 Oct;17(10):4220-7
references: 16870702
references: J Cell Biol. 1983 Feb;96(2):347-53
references: 6300135
references: Science. 2004 May 7;304(5672):875-8
references: 15131307
references: Mol Biol Cell. 2003 May;14(5):1913-22
references: 12802064
references: J Cell Biol. 2007 Jul 2;178(1):141-53
references: 17606871
references: Trends Endocrinol Metab. 2006 May-Jun;17(4):159-65
references: 16595179
references: Mol Biol Cell. 2005 Oct;16(10):4572-83
references: 16079174
references: Dev Biol. 1999 Nov 15;215(2):443-52
references: 10545250
references: J Cell Biol. 1980 Aug;86(2):545-53
references: 6249826
references: J Cell Biol. 2010 Jul 26;190(2):233-45
references: 20660630
references: EMBO Rep. 2011 Dec 01;12(12):1273-9
references: 22081140
references: J Cell Biol. 2004 Nov 8;167(3):505-18
references: 15534002
references: FEBS Lett. 1985 Jan 7;179(2):257-61
references: 3838158
references: Science. 1981 Apr 24;212(4493):443-6
references: 6259734
references: Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10566-70
references: 7937994
references: Dev Cell. 2010 May 18;18(5):737-49
references: 20493808
references: Ageing Res Rev. 2008 Jul;7(3):234-48
references: 18657484
references: Curr Biol. 2008 Jul 22;18(14):1034-43
references: 18635356
references: Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17079-86
references: 20864631
references: J Cell Sci. 2010 Mar 15;123(Pt 6):983-92
references: 20200230
references: Cell Motil Cytoskeleton. 1992;23(2):145-56
references: 1333366
references: EMBO J. 2001 Aug 15;20(16):4490-9
references: 11500376
references: Mol Cell Biol. 2005 Sep;25(18):8393-400
references: 16135826
references: Brain Res Mol Brain Res. 2005 Jul 29;138(1):94-103
references: 15908039
references: Curr Biol. 2008 Oct 28;18(20):1587-1593
references: 18948008
references: Nucleic Acids Res. 2009 Jan;37(Database issue):D515-9
references: 18974179
references: J Biol Chem. 1997 Oct 24;272(43):27313-8
references: 9341180
references: Cell Signal. 2010 Sep;22(9):1274-81
references: 20363320
references: Science. 1990 May 4;248(4955):591-3
references: 2110382
references: EMBO Rep. 2004 Jun;5(6):602-6
references: 15143344
references: J Biol Chem. 2010 Mar 12;285(11):7938-46
references: 20075071
references: Nature. 2009 May 21;459(7245):356-63
references: 19458711
references: Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9761-6
references: 16782813
references: Dev Biol. 1987 Jul;122(1):163-71
references: 3036630
references: J Cell Biochem. 1988 Jul;37(3):285-99
references: 3410887
references: J Biol Chem. 1988 Oct 5;263(28):14538-43
references: 2844774
references: Methods Mol Biol. 2009;571:333-48
references: 19763978
references: Semin Cell Dev Biol. 2011 Oct;22(8):834-41
references: 21821139
references: J Biol Chem. 1996 Feb 16;271(7):3351-4
references: 8631932