Abstract
Stress-activated MAP kinases (SAPKs) respond to a wide variety of stressors. In most cases, the pathways through which specific stress signals are transmitted to the SAPKs are not known. Our recent findings have begun to address two important and related questions. First, do various stresses activate a SAPK through common pathways initiated at the cell surface, or through alternative, intracellular inputs? Second, how does an activated SAPK mount a specific response appropriate to the particular stress experienced? Our work has uncovered the mechanisms by which two stresses, arsenite treatment and DNA damage, stimulate the yeast SAPKs Hog1 and Mpk1, respectively. We found that these stresses activate the SAPKs through intracellular inputs that modulate their basal phosphorylation, rather than by activation of the protein kinase cascades known to stimulate them. Both stresses act through targeting, in different ways, the tyrosine-specific or dual-specificity protein phosphatases that normally maintain the SAPKs in a low-activity state. Previous work has demonstrated that basal signal flux through SAPK pathways is important for the sensitivity and dynamic response to external signals. Our work reveals that basal activity of SAPKs is additionally important to allow SAPK activation by intracellular inputs that modulate that activity. Additionally, because different stressors may activate SAPKs by modulation of basal signal through inputs at distinct nodes along the canonical activation pathway, stress-specific SAPK outputs may be controlled, in part, by the specific intracellular mechanisms of their activation. Thus, understanding the intracellular pathways through which various stressors activate SAPKs is likely to provide insight into how they elicit physiologically coherent responses to the specific stress experienced.
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References
Aguilera J, Rodrígues-Vargas S, Prieto JA (2005) The HOG MAP kinase pathway is required for the induction of methylglyoxal-responsive genes and determines methylglyoxal resistance in Saccharomyces cerevisiae. Mol Microbiol 56:228–239. https://doi.org/10.1111/j.1365-2958.2005.04533.x
Azad GK, Singh V, Thakare MJ, Barawal S, Tomar RS (2014) Mitogen-activated protein kinase Hog1 is activated in response to curcumin exposure in the budding yeast Saccharomyces cerevisiae. BMC Microbiol 14:317–327. https://doi.org/10.1186/s12866-014-0317-0
Babour A, Bicknell AA, Tourtellotte J, Niwa M (2010) A surveillance pathway monitors the fitness of the endoplasmic reticulum to control its inheritance. Cell 142:256–269. https://doi.org/10.1016/j.cell.2010.06.006
Bilsland E, Molin C, Swaminathan S, Ramne A, Sunnerhagen P (2004) Rck1 and Rck2 MAPKAP kinases and the HOG pathway are required for oxidative stress resistance. Mol Micro 53:1743–1756. https://doi.org/10.1111/j.1365-2958.2004.04238.x
Chen Y, Feldman DE, Deng C, Brown JA, De Giacomo AF, Gaw AF, Shi G, Le QT, Brown JM, Koong AC (2005) Identification of mitogen-activated protein kinase signaling pathways that confer resistance to endoplasmic reticulum stress in Saccharomyces cerevisiae. Mol Cancer Res 3:669–677. https://doi.org/10.1158/1541-7786.MCR-05-0181
Han J, Lee J-D, Bibbs L, Ulevitch RJ (1994) A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265:808–811. https://doi.org/10.1126/science.7914033
Jiang L, Cao C, Zhang L, Lin W, Xia J, Xu H, Zhang Y (2014) Cadmium-induced activation of high osmolarity pathway through its Sln1 branch is dependent on the MAP kinase kinase kinase Ssk2, but not its paralog Ssk22, in budding yeast. FEMS Yeast Res 14:1263–1272. https://doi.org/10.1111/1567-1364.12220
Kamada Y, Jung US, Piotrowski J, Levin DE (1995) The protein kinase C-activated MAP kinase pathway of Saccharomyces cerevisiae mediates a novel aspect of the heat shock response. Genes Dev 9:1559–1571. https://doi.org/10.1101/gad.9.13.1559
Klis FM, Mol P, Hellingwerf K, Brul S (2002) Dynamics of cell wall structure in Saccharomyces cerevisiae. FEMS Micro Rev 26:239–256. https://doi.org/10.1111/j.1574-6976.2002.tb00613.x
Lawrence CL, Botting CH, Antrobus R, Coote PJ (2004) Evidence of a new role for the high-osmolarity glycerol mitogen-activated protein kinase pathway in yeast: regulating adaptation to citric acid stress. Mol Cell Biol 24:3307–3323. https://doi.org/10.1128/MCB.24.8.3307-3323.2004
Lee J, Levin DE (2018) Intracellular mechanism by which arsenite activates yeast stress MAPK Hog1. Mol Biol Cell 29:1904–1915. https://doi.org/10.1091/mbc.E18-03-0185
Lee J, Reiter W, Dohnal I, Gregori C, Beese-Sims S, Kuchler K, Ammerer G, Levin DE (2013) MAPK Hog1 closes the S. cerevisiae glycerol channel Fps1 by phosphorylating and displacing its positive regulators. Genes Dev 27:2590–2601. https://doi.org/10.1101/gad.229310.113
Lesage G, Bussey H (2006) Cell wall assembly in Saccharomyces cerevisiae. Micro Mol Biol Rev 70:317–343. https://doi.org/10.1128/MMBR.00038-05
Levin DE (2011) Regulation of cell wall biosynthesis in Saccharomyces cerevisiae: The cell wall integrity signaling pathway. Genetics 189:1145–1175. https://doi.org/10.1534/genetics.111.128264
Liu L, Levin DE (2018) Intracellular mechanism by which genotoxic stress activates yeast SAPK Mpk1. Mol Biol Cell. https://doi.org/10.1091/mbc.E18-07-0441 (Epub ahead of print)
Macia J, Regot S, Peeters T, Conde N, Solé R, Posas F (2009) Dynamic signaling in the Hog1 MAPK pathway relies on high basal signal transduction. Sci Signal. https://doi.org/10.1126/scisignal.2000056
Mollapour M, Piper PW (2006) Hog1p mitogen-activated protein kinase determines acetic acid resistance in Saccharomyces cerevisiae. FEMS Yeast Res 6:1274–1280. https://doi.org/10.1128/MCB.02205-06
Queralt E, Igual JC (2005) Functional connection between the Clb5 cyclin, the protein kinase C pathway and the Swi4 transcription factor in Saccharomyces cerevisiae. Genetics 171:1485–1498.https://doi.org/10.1534/genetics.105.045005
Rehman K, Chen Z, Wang WW, Wang YW, Sakamoto A, Zhang YF, Naranmandura H, Suzuki N (2012) Mechanisms underlying the inhibitory effects of arsenic compounds on protein tyrosine phosphatase (PTP). Toxicol Appl Pharmacol 263:273–280. https://doi.org/10.1016/j.taap.2012.06.019
Saito H, Posas F (2012) Response to hyperosmotic stress. Genetics 192:289–318. https://doi.org/10.1534/genetics.112.140863
Soriano-Carot M, Bañó MC, Igual JC (2012) The yeast mitogen-activated protein kinase Slt2 is involved in the cellular response to genotoxic stress. Cell Div. https://doi.org/10.1186/1747-1028-7-1
Sotelo J, Rodríguez-Gabriel MA (2006) Mitogen-activated protein kinase Hog1 is essential for the response to arsenite in Saccharomyces cerevisiae. Euk Cell 5, 1826–1830. https://doi.org/10.1128/EC.00225-06
Thorsen M, Di Y, Tängemo C, Morillas M, Ahmadpour D, Van der Does C, Wagner A, Johansson E, Boman J, Posas F et al (2006) The MAPK Hog1p modulates Fps1p-dependent arsenite uptake and tolerance in yeast. Mol Biol Cell 17:4400–4410. https://doi.org/10.1091/mbc.e06-04-0315
Truman AW, Millson SH, Nuttall JM, King V, Mollapour M, Prodromou C, Pearl LH, Piper PW (2006) Expressed in the yeast Saccharomyces cerevisiae, human ERK5 is a client of the Hsp90 chaperone that complements loss of the Slt2p (Mpk1p) cell integrity stress-activated protein kinase. Euk Cell 5:1914–1924. https://doi.org/10.1128/EC.00263-06
Vilella F, Herrero E, Torres J, de la Torre-Ruiz MA (2005) Pkc1 and the upstream elements of the cell integrity pathway in Saccharomyces cerevisiae, Rom2 and Mtl1, are required for cellular responses to oxidative stress. J Biol Chem 280:9149–9159. https://doi.org/10.1074/jbc.M411062200
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Supported by NIH Grant R01GM048533 to D.E.L.
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Communicated by M. Kupiec.
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Lee, J., Liu, L. & Levin, D.E. Stressing out or stressing in: intracellular pathways for SAPK activation. Curr Genet 65, 417–421 (2019). https://doi.org/10.1007/s00294-018-0898-5
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DOI: https://doi.org/10.1007/s00294-018-0898-5