Inhibitory GEF Phosphorylation Provides Negative Feedback in the Yeast Polarity Circuit

Kuo, Chun-Chen, Savage, Natasha S ORCID: 0000-0002-6831-6533, Chen, Hsin, Wu, Chi-Fang, Zyla, Trevin R and Lew, Daniel J (2014) Inhibitory GEF Phosphorylation Provides Negative Feedback in the Yeast Polarity Circuit. Current Biology, 24 (7). pp. 753-759.

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Abstract

Cell polarity is critical for the form and function of many celltypes. During polarity establishment, cells define a cortical‘‘front’’ that behaves differently from the rest of the cortex.The front accumulates high levels of the active form ofa polarity-determining Rho-family GTPase (Cdc42, Rac, orRop) that then orients cytoskeletal elements through variouseffectors to generate the polarized morphology appropriateto the particular cell type [1, 2]. GTPase accumulation isthought to involve positive feedback, such that activeGTPase promotes further delivery and/or activation ofmore GTPase in its vicinity [3]. Recent studies suggest thatonce a front forms, the concentration of polarity factors atthe front can increase and decrease periodically, first clus-tering the factors at the cortex and then dispersing themback to the cytoplasm [4–7]. Such oscillatory behaviorimplies the presence of negative feedback in the polaritycircuit [8], but the mechanism of negative feedback wasnot known. Here we show that, in the budding yeastSaccha-romyces cerevisiae, the catalytic activity of the Cdc42-directed GEF is inhibited by Cdc42-stimulated effectorkinases, thus providing negative feedback. We furthershow that replacing the GEF with a phosphosite mutantGEF abolishes oscillations and leads to the accumulationof excess GTP-Cdc42 and other polarity factors at the front.These findings reveal a mechanism for negative feedbackand suggest that the function of negative feedback via GEFinhibition is to buffer the level of Cdc42 at the polarity site.

Item Type:	Article
Additional Information:	## TULIP Type: Articles/Papers (Journal) ##
Uncontrolled Keywords:	Saccharomyces cerevisiae, cdc42 GTP-Binding Protein, Saccharomyces cerevisiae, Guanine Nucleotide Exchange Factors, Signal Transduction, Cell Polarity, Phosphorylation, Models, Biological, Computer Simulation, Feedback, Physiological
Depositing User:	Symplectic Admin
Date Deposited:	10 Apr 2017 06:53
Last Modified:	19 Jan 2023 07:34
DOI:	10.1016/j.cub.2014.02.024
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3002232