The Cdc42p effector Gic2p is targeted for ubiquitin-dependent degradation by the SCFGrr1 complex

Jaquenoud, Malika; Gulli, Marie‐Pierre; Peter, Katrin; Peter, Matthias

doi:10.1093/emboj/17.18.5360

Cited by 92 publications

(102 citation statements)

References 76 publications

(154 reference statements)

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“…The results with Gic2 clearly support a role for the BR domain in polarized localization, as localization to nascent bud sites was abolished by each of the BR domain mutations (⌬BR, N4, or A6), and was restored in the Gic2 PLC␦ and Gic2 Cla4 chimeras ( Figure 7D). Notably, Gic2-GFP x3 levels were actually increased by the BR domain mutations (data not shown), which is consistent with the fact that Cdc42 binding promotes degradation of Gic2 (Jaquenoud et al, 1998). In contrast to these Gic2 phenotypes, none of the Gic1 BR muta- Localization of the isolated membrane-binding domains expressed as galactose-inducible GST-GFP fusions (Cla4, PLC␦, and FAPP1) or GFP fusions (Spo20 and Opi1).…”

Section: Br Domains In the Yeast Cdc42 Effectors Gic1 And Gic2supporting

confidence: 72%

Identification of Novel Membrane-binding Domains in Multiple Yeast Cdc42 Effectors

Takahashi

Pryciak

2007

MBoC

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The Rho-type GTPase Cdc42 is a central regulator of eukaryotic cell polarity and signal transduction. In budding yeast, Cdc42 regulates polarity and mitogen-activated protein (MAP) kinase signaling in part through the PAK-family kinase Ste20. Activation of Ste20 requires a Cdc42/Rac interactive binding (CRIB) domain, which mediates its recruitment to membrane-associated Cdc42. Here, we identify a separate domain in Ste20 that interacts directly with membrane phospholipids and is critical for its function. This short region, termed the basic-rich (BR) domain, can target green fluorescent protein to the plasma membrane in vivo and binds PIP 2 -containing liposomes in vitro. Mutation of basic or hydrophobic residues in the BR domain abolishes polarized localization of Ste20 and its function in both MAP kinase-dependent and independent pathways. Thus, Cdc42 binding is required but is insufficient; instead, direct membrane binding by Ste20 is also required. Nevertheless, phospholipid specificity is not essential in vivo, because the BR domain can be replaced with several heterologous lipid-binding domains of varying lipid preferences. We also identify functionally important BR domains in two other yeast Cdc42 effectors, Gic1 and Gic2, suggesting that cooperation between protein-protein and protein-membrane interactions is a prevalent mechanism during Cdc42-regulated signaling and perhaps for other dynamic localization events at the cell cortex.

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Section: Br Domains In the Yeast Cdc42 Effectors Gic1 And Gic2supporting

confidence: 72%

Identification of Novel Membrane-binding Domains in Multiple Yeast Cdc42 Effectors

Takahashi

Pryciak

2007

MBoC

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“…Function in Cell Polarity-A previous report found that overexpression of the N terminus (amino acids 1-208) of Gic2 under an inducible promoter resulted in large and round cells (9). Therefore, the N terminus of Gic2 may be dominant negative in yeast cells.…”

Section: The N-terminal Polybasic Region Of Gic2 Is Important For Itsmentioning

confidence: 99%

“…Thus, the observed depolarization of gic2 variants was not a result of general loss of cell polarity in the cells. Because Gic2 is specifically expressed shortly before budding and is ubiquitinated and degraded after the small budded stage (7,9), most large budded cells do not have GFP-Gic2 signal. On the other hand, the gic2 variants were frequently found in cells at later stages of the cell cycle.…”

Section: The N-terminal Polybasic Region Of Gic2 Is Important For Itsmentioning

confidence: 99%

“…Gic1 and Gic2 have overlapping functions, as cells that have lost either Gic1 or Gic2 are mostly normal in morphology and growth whereas cells that have lost both Gic proteins have morphological defects (including defects in actin polarization) as well as a severe growth defect at 37°C (5,6). Gic2 is expressed in a cell cycle-dependent manner with its expression peaking during bud emergence, and Gic2 is degraded shortly after bud emergence via ubiquitin-dependent proteolysis (7,9). Binding of Gic2 to GTP-Cdc42 is a prerequisite for degradation, suggesting that Gic2 levels are down-regulated after Gic2 fulfills its role in cell polarization (9).…”

mentioning

confidence: 99%

“…Gic2 is expressed in a cell cycle-dependent manner with its expression peaking during bud emergence, and Gic2 is degraded shortly after bud emergence via ubiquitin-dependent proteolysis (7,9). Binding of Gic2 to GTP-Cdc42 is a prerequisite for degradation, suggesting that Gic2 levels are down-regulated after Gic2 fulfills its role in cell polarization (9).…”

mentioning

confidence: 99%

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Regulation of Gic2 Localization and Function by Phosphatidylinositol 4,5-Bisphosphate during the Establishment of Cell Polarity in Budding Yeast

Orlando

Zhang

et al. 2008

Journal of Biological Chemistry

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Establishment of cell polarity is important for a wide range of biological processes, from asymmetric cell growth in budding yeast to neurite formation in neurons. In the yeast Saccharomyces cerevisiae, the small GTPase Cdc42 controls polarized actin organization and exocytosis toward the bud. Gic2, a Cdc42 effector, is targeted to the bud tip and plays an important role in early bud formation. The GTP-bound Cdc42 interacts with Gic2 through the Cdc42/Rac interactive binding domain located at the N terminus of Gic2 and activates Gic2 during bud emergence. Here we identify a polybasic region in Gic2 adjacent to the Cdc42/Rac interactive binding domain that directly interacts with phosphatidylinositol 4,5-bisphosphate in the plasma membrane. We demonstrate that this interaction is necessary for the polarized localization of Gic2 to the bud tip and is important for the function of Gic2 in cell polarization. We propose that phosphatidylinositol 4,5-bisphosphate and Cdc42 act in concert to regulate polarized localization and function of Gic2 during polarized cell growth in the budding yeast.Generation of cell polarity is critical for many basic cellular functions such as nutrient transport across epithelial cells and neuronal transmission in neurons. Cell polarization generally occurs by the delivery of proteins and lipids to specific sites on the plasma membrane (PM), 4 thus generating distinct cellular domains. Budding yeast is an excellent model organism for the study of cell polarity because polarized actin organization and membrane traffic are important for bud formation and major proteins involved in cell polarization are conserved in higher eukaryotes (1-3). Cdc42, a member of the Rho family of small GTP-binding proteins and a master regulator of cell polarity, controls polarized organization of actin cables and the exocytosis machinery for bud emergence and enlargement (3, 4). Gic2, and its homolog, Gic1, are a pair of Cdc42 effectors that each contain an N-terminal Cdc42/Rac Interactive Binding (CRIB) domain, which interacts with GTP-bound Cdc42 (5, 6). Deletion of GIC1 and GIC2 together, but not either one alone, causes cells to arrest in large, round, and unbudded morphologies at 37°C, indicative of the loss of cell polarity (5, 6). Gic2 is localized to the site of bud emergence and at tips of small buds in yeast and is required for polarized actin organization during budding at 37°C (5, 6). Gic2 is thought to function in polarized growth by linking activated Cdc42 to proteins that regulate actin organization, such as Bni1, Spa2, and Bud6 (7). Recently, it was shown that Gic1 and Gic2 are also involved in the recruitment of septins to the presumptive bud site at the beginning of the cell cycle (8). Gic1 and Gic2 have overlapping functions, as cells that have lost either Gic1 or Gic2 are mostly normal in morphology and growth whereas cells that have lost both Gic proteins have morphological defects (including defects in actin polarization) as well as a severe growth defect at 37°C (5, 6). Gic2 is expressed ...

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Ubiquitin-mediated proteolysis of vertebrate G1- and S-phase regulators

Yew

2001

J. Cell. Physiol.

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Cell-cycle progression in all eukaryotes is driven by cyclin-dependent kinases (CDKs) and their cyclin partners. In vertebrates, the proper and timely duplication of the genome during S-phase relies on the coordinated activities of positive regulators such as CDK±cyclins and E2F, and negative regulators such as CDK inhibitors of the Cip/Kip and INK4 families. Recent and ongoing work indicates that many important regulators of G1-and S-phases are targeted for ubiquitination and subsequent degradation by the 26S proteasome. The proteolysis of key proteins during G1-and S-phases appears to be central for proper custodial regulation of DNA replication and the maintenance of cellular homeostasis in general. This review highlights the current literature regarding ubiquitin-mediated proteolysis of G1-and S-phase regulators and the control of events during the initiation and completion of DNA replication in vertebrates.

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The Cdc42p effector Gic2p is targeted for ubiquitin-dependent degradation by the SCFGrr1 complex

Cited by 92 publications

References 76 publications

Identification of Novel Membrane-binding Domains in Multiple Yeast Cdc42 Effectors

Identification of Novel Membrane-binding Domains in Multiple Yeast Cdc42 Effectors

Regulation of Gic2 Localization and Function by Phosphatidylinositol 4,5-Bisphosphate during the Establishment of Cell Polarity in Budding Yeast

Ubiquitin-mediated proteolysis of vertebrate G1- and S-phase regulators

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