A Systems-Biology Analysis of Feedback Inhibition in the Sho1 Osmotic-Stress-Response Pathway

Nan Hao, Marcelo Behar, Stephen C. Parnell, Matthew P. Torres, Christoph H. Borchers, Timothy C C. Elston, Henrik G. Dohlman

Research output: Contribution to journalArticlepeer-review

84 Citations (Scopus)

Abstract

Background: A common property of signal transduction systems is that they rapidly lose their ability to respond to a given stimulus. For instance in yeast, the mitogen-activated protein (MAP) kinase Hog1 is activated and inactivated within minutes, even when the osmotic-stress stimulus is sustained. Results: Here, we used a combination of experimental and computational analyses to investigate the dynamic behavior of Hog1 activation in vivo. Computational modeling suggested that a negative-feedback loop operates early in the pathway and leads to rapid attenuation of Hog1 signaling. Experimental analysis revealed that the membrane-bound osmosensor Sho1 is phosphorylated by Hog1 and that phosphorylation occurs on Ser-166. Moreover, Sho1 exists in a homo-oligomeric complex, and phosphorylation by Hog1 promotes a transition from the oligomeric to monomeric state. A phosphorylation-site mutation (Sho1S166E) diminishes the formation of Sho1-oligomers, dampens activation of the Hog1 kinase, and impairs growth in high-salt or sorbitol conditions. Conclusions: These findings reveal a novel phosphorylation-dependent feedback loop leading to diminished cellular responses to an osmotic-stress stimulus.

Original languageEnglish
Pages (from-to)659-667
Number of pages9
JournalCurrent Biology
Volume17
Issue number8
DOIs
Publication statusPublished - 17 Apr 2007
Externally publishedYes

Keywords

  • SIGNALING

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