Inhibitory GEF phosphorylation provides negative feedback in the yeast polarity circuit
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Cell polarity is critical for the form and function of many cell types. 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 of a polarity-determining Rho-family GTPase (Cdc42, Rac, or Rop) that then orients cytoskeletal elements through various effectors to generate the polarized morphology appropriate to the particular cell type [1, 2]. GTPase accumulation is thought to involve positive feedback, such that active GTPase promotes further delivery and/or activation of more GTPase in its vicinity . Recent studies suggest that once a front forms, the concentration of polarity factors at the front can increase and decrease periodically, first clustering the factors at the cortex and then dispersing them back to the cytoplasm [4-7]. Such oscillatory behavior implies the presence of negative feedback in the polarity circuit , but the mechanism of negative feedback was not known. Here we show that, in the budding yeast Saccharomyces cerevisiae, the catalytic activity of the Cdc42-directed GEF is inhibited by Cdc42-stimulated effector kinases, thus providing negative feedback. We further show that replacing the GEF with a phosphosite mutant GEF abolishes oscillations and leads to the accumulation of excess GTP-Cdc42 and other polarity factors at the front. These findings reveal a mechanism for negative feedback and suggest that the function of negative feedback via GEF inhibition is to buffer the level of Cdc42 at the polarity site. © 2014 Elsevier Ltd.
Published Version (Please cite this version)10.1016/j.cub.2014.02.024
Publication InfoChen, H; Kuo, CC; Lew, Daniel J; Savage, NS; Wu, CF; & Zyla, Trevin (2014). Inhibitory GEF phosphorylation provides negative feedback in the yeast polarity circuit. Current Biology, 24(7). pp. 753-759. 10.1016/j.cub.2014.02.024. Retrieved from http://hdl.handle.net/10161/13038.
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James B. Duke Professor of Pharmacology and Cancer Biology
Our research interests encompass questions on cell cycle control, the control of cell polarity, and the specification of distinct cortical domains within cells. We are also trying to understand how cells can monitor their shape and react to environmental influences that affect cytoskeletal behavior. One focus is the study of how the Cyclin Dependent Kinases (CDKs) that control cell cycle progression act to promote specific changes in cell polarity. A ras-related G protein