Inhibitory GEF phosphorylation provides negative feedback in the yeast polarity circuit.

Journal Article (Journal Article)

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 [3]. 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 [8], 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.

Full Text

Duke Authors

Cited Authors

  • Kuo, C-C; Savage, NS; Chen, H; Wu, C-F; Zyla, TR; Lew, DJ

Published Date

  • March 31, 2014

Published In

Volume / Issue

  • 24 / 7

Start / End Page

  • 753 - 759

PubMed ID

  • 24631237

Pubmed Central ID

  • PMC4018745

Electronic International Standard Serial Number (EISSN)

  • 1879-0445

Digital Object Identifier (DOI)

  • 10.1016/j.cub.2014.02.024


  • eng

Conference Location

  • England