Modeling mutant phenotypes and oscillatory dynamics in the Saccharomyces cerevisiae cAMP-PKA pathway
Tóm tắt
The cyclic AMP-Protein Kinase A (cAMP-PKA) pathway is an evolutionarily conserved signal transduction mechanism that regulates cellular growth and differentiation in animals and fungi. We present a mathematical model that recapitulates the short-term and long-term dynamics of this pathway in the budding yeast, Saccharomyces cerevisiae. Our model is aimed at recapitulating the dynamics of cAMP signaling for wild-type cells as well as single (pde1 Δ and pde2 Δ) and double (pde1 Δ pde2 Δ) phosphodiesterase mutants. Our model focuses on PKA-mediated negative feedback on the activity of phosphodiesterases and the Ras branch of the cAMP-PKA pathway. We show that both of these types of negative feedback are required to reproduce the wild-type signaling behavior that occurs on both short and long time scales, as well as the the observed responses of phosphodiesterase mutants. A novel feature of our model is that, for a wide range of parameters, it predicts that intracellular cAMP concentrations should exhibit decaying oscillatory dynamics in their approach to steady state following glucose stimulation. Experimental measurements of cAMP levels in two genetic backgrounds of S. cerevisiae confirmed the presence of decaying cAMP oscillations as predicted by the model. Our model of the cAMP-PKA pathway provides new insights into how yeast respond to alterations in their nutrient environment. Because the model has both predictive and explanatory power it will serve as a foundation for future mathematical and experimental studies of this important signaling network.
Tài liệu tham khảo
Fimia GM, Sassone-Corsi P: Cyclic AMP signalling. J Cell Sci. 2001, 114 (Pt 11): 1971-1972.
Beavo JA, Brunton LL: Cyclic nucleotide research – still expanding after half a century. Nat Rev Mol Cell Biol. 2002, 3 (9): 710-718. 10.1038/nrm911.
Holz GG, Kang G, Harbeck M, Roe MW, Chepurny OG: Cell physiology of cAMP sensor Epac. J Physiol. 2006, 577 (Pt 1): 5-15. [http://dx.doi.org/10.1113/jphysiol.2006.119644]
Rall TW, Sutherland EW: Formation of a cyclic adenine ribonucleotide by tissue particles. J Biol Chem. 1958, 232 (2): 1065-1076.
Carlone DL, Richards JS: Functional interactions, phosphorylation, and levels of 3’,5’-cyclic adenosine monophosphate-regulatory element binding protein and steroidogenic factor-1 mediate hormone-regulated and constitutive expression of aromatase in gonadal cells. Mol Endocrinol. 1997, 11 (3): 292-304. 10.1210/me.11.3.292.
Buck LB: Information coding in the vertebrate olfactory system. Annu Rev Neurosci. 1996, 19: 517-544. 10.1146/annurev.ne.19.030196.002505. [http://dx.doi.org/10.1146/annurev.ne.19.030196.002505] 10.1146/annurev.ne.19.030196.002505
Walsh DA, Perkins JP, Krebs EG: An adenosine 3’,5’-monophosphate-dependant protein kinase from rabbit skeletal muscle. J Biol Chem. 1968, 243 (13): 3763-3765.
Hong S, Bang S, Hyun S, Kang J, Jeong K, Paik D, Chung J, Kim J: cAMP signalling in mushroom bodies modulates temperature preference behaviour in Drosophila. Nature. 2008, 454 (7205): 771-775. [http://dx.doi.org/10.1038/nature07090]
Haynes RC, Sutherland EW, Rall TW: The role of cyclic adenylic acid in hormone action. Recent Prog Horm Res. 1960, 16: 121-138.
Thevelein JM, de Winde JH: Novel sensing mechanisms and targets for the cAMP-protein kinase A pathway in the yeast Saccharomyces cerevisiae. Mol Microbiol. 1999, 33 (5): 904-918. 10.1046/j.1365-2958.1999.01538.x.
Toda T, Uno I, Ishikawa T, Powers S, Kataoka T, Broek D, Cameron S, Broach J, Matsumoto K, Wigler M: In yeast, RAS proteins are controlling elements of adenylate cyclase. Cell. 1985, 40: 27-36. 10.1016/0092-8674(85)90305-8.
Kraakman L, Lemaire K, Ma P, Teunissen AW, Donaton MC, Dijck PV, Winderickx J, de Winde JH, Thevelein JM: A Saccharomyces cerevisiae G-protein coupled receptor, Gpr1, is specifically required for glucose activation of the cAMP pathway during the transition to growth on glucose. Mol Microbiol. 1999, 32 (5): 1002-1012. 10.1046/j.1365-2958.1999.01413.x.
van Aelst, Jans AW, Thevelein JM: Involvement of the CDC25 gene product in the signal transmission pathway of the glucose-induced RAS-mediated cAMP signal in the yeast Saccharomyces cerevisiae. J Gen Microbiol. 1991, 137 (2): 341-349. 10.1099/00221287-137-2-341.
Broek D, Toda T, Michaeli T, Levin L, Birchmeier C, Zoller M, Powers S, Wigler M: The S. cerevisiae CDC25 gene product regulates the RAS/adenylate cyclase pathway. Cell. 1987, 48 (5): 789-799. 10.1016/0092-8674(87)90076-6.
Créchet JB, Poullet P, Mistou MY, Parmeggiani A, Camonis J, Boy-Marcotte E, Damak F, Jacquet M: Enhancement of the GDP-GTP exchange of RAS proteins by the carboxyl-terminal domain of SCD25. Science. 1990, 248 (4957): 866-868. 10.1126/science.2188363.
Boy-Marcotte E, Ikonomi P, Jacquet M: SDC25, a dispensable Ras guanine nucleotide exchange factor of Saccharomyces cerevisiae differs from CDC25 by its regulation. Mol Biol Cell. 1996, 7 (4): 529-539.
Paiardi C, Belotti F, Colombo S, Tisi R, Martegani E: The large N-terminal domain of Cdc25 protein of the yeast Saccharomyces cerevisiae is required for glucose-induced Ras2 activation. FEMS Yeast Res. 2007, 7 (8): 1270-1275. 10.1111/j.1567-1364.2007.00300.x. [http://dx.doi.org/10.1111/j.1567-1364.2007.00300.x] 10.1111/j.1567-1364.2007.00300.x
Colombo S, Ma P, Cauwenberg L, Winderickx J, Crauwels M, Teunissen A, Nauwelaers D, de Winde JH, Gorwa MF, Colavizza D, Thevelein JM: Involvement of distinct G-proteins, Gpa2 and Ras, in glucose and intracellular acidification-induced cAMP signalling in the yeast Saccharomyces cerevisiae. EMBO J. 1998, 17 (12): 3326-3341. 10.1093/emboj/17.12.3326. [http://dx.doi.org/10.1093/emboj/17.12.3326] 10.1093/emboj/17.12.3326
Colombo S, Ronchetti D, Thevelein JM, Winderickx J, Martegani E: Activation state of the Ras2 protein and glucose-induced signaling in Saccharomyces cerevisiae. J Biol Chem. 2004, 279 (45): 46715-46722. 10.1074/jbc.M405136200. [http://dx.doi.org/10.1074/jbc.M405136200] 10.1074/jbc.M405136200
Thevelein JM, Bonini B, Castermans D, Haesendonckx S, Kriel J, Louwet W, Thayumanavan P, Popova Y, Rubio-Texeira M, Schepers W, Vandormael P, Zeebroeck GV, Verhaert P, Versele M, Voordeckers K: Novel mechanisms in nutrient activation of the yeast protein kinase A pathway. Acta Microbiol Immunol Hung. 2008, 55 (2): 75-89. 10.1556/AMicr.55.2008.2.1. [http://dx.doi.org/10.1556/AMicr.55.2008.2.1] 10.1556/AMicr.55.2008.2.1
Tanaka K, Matsumoto K, Toh-E A: IRA1, an inhibitory regulator of the RAS-cyclic AMP pathway in Saccharomyces cerevisiae. Mol Cell Biol. 1989, 9 (2): 757-768.
Tanaka K, Nakafuku M, Tamanoi F, Kaziro Y, Matsumoto K, Toh-e A: IRA2, a second gene of Saccharomyces cerevisiae that encodes a protein with a domain homologous to mammalian Ras GTPase-activating protein. Mol Cell Biol. 1990, 10 (8): 4303-4313.
Rolland F, Winde JHD, Lemaire K, Boles E, Thevelein JM, Winderickx J: Glucose-induced cAMP signalling in yeast requires both a G-protein coupled receptor system for extracellular glucose detection and a separable hexose kinase-dependent sensing process. Mol Microbiol. 2000, 38 (2): 348-358. 10.1046/j.1365-2958.2000.02125.x.
Santangelo GM: Glucose signaling in Saccharomyces cerevisiae. Microbiol Mol Biol Rev. 2006, 70: 253-282. 10.1128/MMBR.70.1.253-282.2006. [http://dx.doi.org/10.1128/MMBR.70.1.253-282.2006] 10.1128/MMBR.70.1.253-282.2006
Versele M, de Winde JH, Thevelein JM: A novel regulator of G protein signalling in yeast, Rgs2, downregulates glucose-activation of the cAMP pathway through direct inhibition of Gpa2. EMBO J. 1999, 18 (20): 5577-5591. 10.1093/emboj/18.20.5577. [http://dx.doi.org/10.1093/emboj/18.20.5577] 10.1093/emboj/18.20.5577
Kehrl J, Sinnarajah S: RGS2: a multifunctional regulator of G-protein signaling. Int J Biochem Cell Biol. 2002, 34 (5): 432-438. 10.1016/S1357-2725(01)00141-8.
Toda T, Cameron S, Sass P, Zoller M, Scott JD, McMullen B, Hurwitz M, Krebs EG, Wigler M: Cloning and characterization of BCY1, a locus encoding a regulatory subunit of the cyclic AMP-dependent protein kinase in Saccharomyces cerevisiae. Mol Cell Biol. 1987, 7 (4): 1371-1377.
Toda T, Cameron S, Sass P, Zoller M, Wigler M: Three different genes in S.cerevisiae encode the catalytic subunits of the cAMP-dependent protein kinase. Cell. 1987, 50 (2): 277-287. 10.1016/0092-8674(87)90223-6.
Gill GN, Garren LD: Role of the receptor in the mechanism of action of adenosine 3’:5’-cyclic monophosphate. Proc Natl Acad Sci U S A. 1971, 68 (4): 786-790. 10.1073/pnas.68.4.786.
Proud CG, Rylatt DB, Yeaman SJ, Cohen P: Amino acid sequences at the two sites on glycogen synthetase phosphorylated by cyclic AMP-dependent protein kinase and their dephosphorylation by protein phosphatase-III. FEBS Lett. 1977, 80 (2): 435-442. 10.1016/0014-5793(77)80493-6.
Fang X, Yu SX, Lu Y, Bast RCJr, Woodgett JR, Mills GB: Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc Natl Acad Sci U S A. 2000, 97 (22): 11960-1165. 10.1073/pnas.220413597.
Taylor SS, Buechler JA, Yonemoto W: cAMP-dependent protein kinase: framework for a diverse family of regulatory enzymes. Annu Rev Biochem. 1990, 59: 971-1005. 10.1146/annurev.bi.59.070190.004543. [http://dx.doi.org/10.1146/annurev.bi.59.070190.004543] 10.1146/annurev.bi.59.070190.004543
Francis SH, Corbin JD: Structure and function of cyclic nucleotide-dependent protein kinases. Annu Rev Physiol. 1994, 56: 237-272. 10.1146/annurev.ph.56.030194.001321. [http://dx.doi.org/10.1146/annurev.ph.56.030194.001321] 10.1146/annurev.ph.56.030194.001321
Mitsuzawa H: Responsiveness to exogenous cAMP of a Saccharomyces cerevisiae strain conferred by naturally occurring alleles of PDE1 and PDE2. Genetics. 1993, 135 (2): 321-326.
Ma P, Wera S, Dijck PV, Thevelein JM: The PDE1-encoded low-affinity phosphodiesterase in the yeast Saccharomyces cerevisiae has a specific function in controlling agonist-induced cAMP signaling. Mol Biol Cell. 1999, 10: 91-104.
Conti M, Beavo J: Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem. 2007, 76: 481-511. 10.1146/annurev.biochem.76.060305.150444. [http://dx.doi.org/10.1146/annurev.biochem.76.060305.150444] 10.1146/annurev.biochem.76.060305.150444
Park J, Grant CM, Dawes IW: The high-affinity cAMP phosphodiesterase of Saccharomyces cerevisiae is the major determinant of cAMP levels in stationary phase: involvement of different branches of the Ras-cyclic AMP pathway in stress responses. Biochem Biophys Res Commun. 2005, 327: 311-319. 10.1016/j.bbrc.2004.12.019. [http://dx.doi.org/10.1016/j.bbrc.2004.12.019] 10.1016/j.bbrc.2004.12.019
Wilson D, Fiori A, Brucker KD, Dijck PV, Stateva L: Candida albicans Pde1p and Gpa2p comprise a regulatory module mediating agonist-induced cAMP signalling and environmental adaptation. Fungal Genet Biol. 2010, 47 (9): 742-752. 10.1016/j.fgb.2010.06.006.
Gonze D, Goldbeter MJA: Stochastic modelling of nucleocytoplasmic oscillations of the transcription factor Msn2 in yeast. J R Soc Interface. 2008, 5 (Suppl 1): S95-S109. [http://dx.doi.org/10.1098/rsif.2008.0141.focus]
Cazzaniga P, Pescini D, Besozzi D, Mauri G, Colombo S, Martegani E: Modeling and stochastic simulation of the Ras/cAMP/PKA pathway in the yeast Saccharomyces cerevisiae evidences a key regulatory function for intracellular guanine nucleotides pools. J Biotechnol. 2008, 133 (3): 377-385. 10.1016/j.jbiotec.2007.09.019. [http://dx.doi.org/10.1016/j.jbiotec.2007.09.019] 10.1016/j.jbiotec.2007.09.019
Williamson T, Schwartz J, Kell DB, Stateva L: Deterministic mathematical models of the cAMP pathway in Saccharomyces cerevisiae. BMC Syst Biol. 2009, 3: 70-10.1186/1752-0509-3-70. [http://dx.doi.org/10.1186/1752-0509-3-70] 10.1186/1752-0509-3-70
Garmendia-Torres C, Goldbeter A, Jacquet M: Nucleocytoplasmic oscillations of the yeast transcription factor Msn2: evidence for periodic PKA activation. Current Biol. 2007, 17: 1044-1049. 10.1016/j.cub.2007.05.032.
Görner W, Durchschlag E, Martinez-Pastor MT, Estruch F, Ammerer G, Hamilton B, Ruis H, Schüller C: Nuclear localization of the C2H2 zinc finger protein Msn2p is regulated by stress and protein kinase A activity. Genes Dev. 1998, 12 (4): 586-597. 10.1101/gad.12.4.586. [http://genesdev.cshlp.org/content/12/4/586.long] 10.1101/gad.12.4.586
Hu Y, Liu E, Bai X, Zhang A: The localization and concentration of the PDE2-encoded high-affinity cAMP phosphodiesterase is regulated by cAMP-dependent protein kinase A in the yeast Saccharomyces cerevisiae. FEMS Yeast Res. 2010, 10 (2): 177-187. 10.1111/j.1567-1364.2009.00598.x.
Lacal JC, McCormick F: The Ras Superfamily of GTPases. 1993, CRC Press
Pardo LA, Lazo PS, Ramos S: Activation of adenylate cyclase in Cdc25 mutants of Saccharomyces cerevisiae. FEBS Lett. 1993, 319 (3): 237-243. 10.1016/0014-5793(93)80554-8.
Garreau H, Geymonat M, Renault G, Jacquet M: Membrane-anchoring domains of Cdc25p, a Saccharomyces cerevisiae Ras exchange factor. Biol Cell. 1996, 86 (2-3): 93-102. 10.1016/0248-4900(96)84771-X.
Mintzer KA, Field J: The SH3 domain of the S. cerevisiae Cdc25p binds adenylyl cyclase and facilitates Ras regulation of cAMP signalling. Cell Signal. 1999, 11 (2): 127-135. 10.1016/S0898-6568(98)00044-8.
Gross E, Goldberg D, Levitzki A: Phosphorylation of the S. cerevisiae Cdc25 in response to glucose results in its dissociation from Ras. Nature. 1992, 360 (6406): 762-765. 10.1038/360762a0. [http://dx.doi.org/10.1038/360762a0] 10.1038/360762a0
Gross A, Winograd S, Marbach I, Levitzki A: The N-terminal half of Cdc25 is essential for processing glucose signaling in Saccharomyces cerevisiae. Biochemistry. 1999, 38 (40): 13252-13262. 10.1021/bi9909849.
Segel I H: Enzyme Kinetics: Behavior and Analysis of Rapid Equilibrium and Steady-State Enzyme Systems. 1993, New York: John Wiley and Sons Inc.
Belotti F, Tisi R, Paiardi C, Rigamonti M, Groppi S, Martegani E: Localization of Ras signaling complex in budding yeast. Biochim Biophys Acta. 2012, 1823 (7): 1208-1216. 10.1016/j.bbamcr.2012.04.016.
Gimeno CJ, Ljungdahl PO, Styles CA, Fink GR: Unipolar cell divisions in the yeast S. cerevisiae lead to filamentous growth: regulation by starvation and RAS. Cell. 1992, 68 (6): 1077-1090. 10.1016/0092-8674(92)90079-R.
Lorenz MC, Heitman J: Yeast pseudohyphal growth is regulated by GPA2, a G protein alpha homolog. EMBO J. 1997, 16 (23): 7008-7018. 10.1093/emboj/16.23.7008. [http://dx.doi.org/10.1093/emboj/16.23.7008] 10.1093/emboj/16.23.7008
Dyachok O, Idevall-Hagren O, Sagetorp J, Tian G, Wuttke A, Arrieumerlou C, Akusjarvi G, Gylfe E, Tengholm A: Glucose-induced cyclic AMP oscillations regulate pulsatile insulin secretion. Cell Metab. 2008, 8: 26-37. 10.1016/j.cmet.2008.06.003. [http://dx.doi.org/10.1016/j.cmet.2008.06.003] 10.1016/j.cmet.2008.06.003
Gorbunova Y, Spitzer NC: Dynamic interactions of cyclic AMP transients and spontaneous Ca(2+) spikes. Nature. 2002, 418 (6893): 93-96. 10.1038/nature00835. [http://dx.doi.org/10.1038/nature00835] 10.1038/nature00835
Maeda M, Lu S, Shaulsky G, Miyazaki Y, Kuwayama H, Tanaka Y, Kuspa A, Loomis WF: Periodic signaling controlled by an oscillatory circuit that includes protein kinases ERK2 and PKA. Science. 2004, 304 (5672): 875-878. 10.1126/science.1094647. [http://dx.doi.org/10.1126/science.1094647] 10.1126/science.1094647
Dyachok O, Sagetorp J, Isakov Y, Tengholm A: cAMP oscillations restrict protein kinase A redistribution in insulin-secreting cells. Biochem Soc Trans. 2006, 34 (Pt 4): 498-501. [http://dx.doi.org/10.1042/BST0340498]
Hao N, O’Shea EK: Signal-dependent dynamics of transcription factor translocation controls gene expression. Nat Struct Mol Biol. 2012, 19: 31-39.
Cai L, Dalal CK, Elowitz MB: Frequency-modulated nuclear localization bursts coordinate gene regulation. Nature. 2008, 455 (7212): 485-490. 10.1038/nature07292.
Drees BL, Thorsson V, Carter GW, Rives AW, Raymond MZ, Avila-Campillo I, Shannon P, Galitski T: Derivation of genetic interaction networks from quantitative phenotype data. Genome Biol. 2005, 6 (4): R38-10.1186/gb-2005-6-4-r38. [http://dx.doi.org/10.1186/gb-2005-6-4-r38] 10.1186/gb-2005-6-4-r38
Moré JJ, Sorensen DC, Hillstrom KE, Garbow BS: The MINPACK Project. Sources and Development of Mathematical Software. Edited by: Cowell WJ, Cowell WJ. 1984, Englewood Cliffs: Prentice-Hall
Jorgensen P, Nishikawa JL, Breitkreutz BJ, Tyers M: Systematic identification of pathways that couple cell growth and division in yeast. Science. 2002, 297 (5580): 395-400. 10.1126/science.1070850.