Stressing out or stressing in: intracellular pathways for SAPK activation
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.
KeywordsHog1 Mpk1 Protein tyrosine phosphatase Dual-specificity phosphatase Arsenite Genotoxic stress Basal signal
Supported by NIH Grant R01GM048533 to D.E.L.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 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 CrossRefGoogle Scholar
- 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 CrossRefGoogle Scholar
- 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 CrossRefGoogle Scholar
- 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 CrossRefGoogle Scholar
- 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 CrossRefGoogle Scholar
- 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 CrossRefGoogle Scholar
- 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 CrossRefGoogle Scholar