Parallel feedback loops control the basal activity of the HOG MAPK signaling cascade.
Tight regulation of the MAP kinase Hog1 is crucial for survival under changing osmotic conditions. Interestingly, we found that Hog1 phosphorylates multiple upstream components, implying feedback regulation within the signaling cascade. Taking advantage of an unexpected link between glucose availability and Hog1 activity, we used quantitative single cell measurements and computational modeling to unravel feedback regulation operating in addition to the well-known adaptation feedback triggered by glycerol accumulation. Indeed, we found that Hog1 phosphorylates its activating kinase Ssk2 on several sites, and cells expressing a non-phosphorylatable Ssk2 mutant are partially defective for feedback regulation and proper control of basal Hog1 activity. Together, our data suggest that Hog1 activity is controlled by intertwined regulatory mechanisms operating with varying kinetics, which together tune the Hog1 response to balance basal Hog1 activity and its steady-state level after adaptation to high osmolarity.
Institute of Biochemistry, Department of Biology, ETH Zürich, Zürich, Switzerland. matthias.peter@bc.biol.ethz.ch.
Hoda
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Sharifian
Fabienne
F
Lampert
Klement
K
Stojanovski
Sergi
S
Regot
Stefania
S
Vaga
Raymond
R
Buser
Sung Sik
SS
Lee
Heinz
H
Koeppl
Francesc
F
Posas
Serge
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Pelet
Matthias
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Peter
D003198:Computer Simulation; D025461:Feedback, Physiological / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D064587:Osmoregulation / Q000502:physiology*; D009997:Osmotic Pressure / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
D029701:Saccharomyces cerevisiae Proteins; C088589:HOG1 protein, S cerevisiae; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose