A Gβγ Effector, ElmoE, Transduces GPCR Signaling to the Actin Network during Chemotaxis

Yan, Jing; Mihaylov, Vassil A.; Xu, Xuehua; Brzostowski, Joseph; Li, Hongyan; Liu, Lunhua; Veenstra, Timothy D.; Parent, Carole A.; Jin, Tian

doi:10.1016/j.devcel.2011.11.007

Cited by 72 publications

(78 citation statements)

References 53 publications

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“…S1A). Mass spectrometry (MS) analysis revealed that p40 and p9 were Gα4 and Gγ, respectively; p240 was ElmoE, which is a known Gβ-binding protein (18); and p30 was a previously uncharacterized protein encoded by DDB_G0271086 and designated as Gip1. Gip1 contained a pleckstrin homology (PH) domain at the N terminus between amino acids 1-109 and an unidentified region at the C terminus.…”

Section: Resultsmentioning

confidence: 99%

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Heterotrimeric G-protein shuttling via Gip1 extends the dynamic range of eukaryotic chemotaxis

Kamimura

Miyanaga

Ueda

2016

Proc. Natl. Acad. Sci. U.S.A.

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Chemotactic eukaryote cells can sense chemical gradients over a wide range of concentrations via heterotrimeric G-protein signaling; however, the underlying wide-range sensing mechanisms are only partially understood. Here we report that a novel regulator of G proteins, G protein-interacting protein 1 (Gip1), is essential for extending the chemotactic range of Dictyostelium cells. Genetic disruption of Gip1 caused severe defects in gradient sensing and directed cell migration at high but not low concentrations of chemoattractant. Also, Gip1 was found to bind and sequester G proteins in cytosolic pools. Receptor activation induced G-protein translocation to the plasma membrane from the cytosol in a Gip1-dependent manner, causing a biased redistribution of G protein on the membrane along a chemoattractant gradient. These findings suggest that Gip1 regulates G-protein shuttling between the cytosol and the membrane to ensure the availability and biased redistribution of G protein on the membrane for receptor-mediated chemotactic signaling. This mechanism offers an explanation for the wide-range sensing seen in eukaryotic chemotaxis.eukaryotic chemotaxis | gradient sensing | dynamic range extension | heterotrimeric G protein C hemotaxis in eukaryotic cells is observed in many physiological processes including embryogenesis, neuronal wiring, wound healing, and immune responses (1, 2). Chemotactic cells share basic properties including high sensitivity to shallow gradients and responsiveness to a wide dynamic range of chemoattractants (3, 4). For instance, human neutrophils and Dictyostelium cells can sense spatial differences in chemoattractant concentration across the cell body in shallow gradients as low as 2% and exhibit chemotaxis over a 10 5 -10 6 -fold range of background concentrations (5-7). Thus, wide-range sensing and adaptation are critical features of chemotaxis as well as other sensory systems such as visual signal transduction (8). However, the underlying regulatory mechanisms in eukaryotic chemotaxis remain unclear.The molecular mechanisms of chemotaxis are evolutionarily conserved among many eukaryotes that use G protein-coupled receptors (GPCRs) and heterotrimeric G proteins to detect chemoattractant gradients (3, 4). In Dictyostelium cells, extracellular cAMP works as a chemoattractant, and binding to its receptor cyclic AMP receptor 1 (cAR1) activates G proteins (Gα2Gβγ) along the concentration gradient, leading to the activation of multiple signaling cascades including the PI3K-PTEN, TorC2-PDK-PKB, phospholipase A2, and guanylyl cyclase pathways. In contrast to the spatial distributions of cAMP/cAR1 association and G-protein activation, downstream signaling pathways are activated in an extremely biased manner at the anterior or posterior of the cell (3, 4). For example, localized patches of phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) are generated at the plasma membrane by an intracellular signal transduction excitable network (STEN) and function as a cue to control the pseudopod formation of...

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Section: Resultsmentioning

confidence: 99%

“…1A). ElmoE associates with Gβγ and serves as a guanine nucleotide exchange factor for Rac to control F-actin in pseudopods (18). Because the interaction between G proteins and ElmoE was unaffected in gip1Δ cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Heterotrimeric G-protein shuttling via Gip1 extends the dynamic range of eukaryotic chemotaxis

Kamimura

Miyanaga

Ueda

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Today, the asymmetric distribution of PIP3 is no longer considered to be the immediate signal responsible for directing actin polymerization in moving cells. Recently, a complex of Elmo/Dock proteins was shown to directly link the G bg component of Dictyostelium chemoattractant receptors to Rac activation of the actin cytoskeleton during chemotaxis [55]. Lockley et al [56] were able to reduce the Meinhardt model described earlier to two variables and to fit it to experimental data of randomly migrating Dictyostelium cells, and cells orienting in a gradient of mechanical shear flow.…”

Section: Actin Polymerization In Response To Extracellular Signalsmentioning

confidence: 99%

Progress and perspectives in signal transduction, actin dynamics, and movement at the cell and tissue level: lessons fromDictyostelium

2016

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Movement of cells and tissues is a basic biological process that is used in development, wound repair, the immune response to bacterial invasion, tumour formation and metastasis, and the search for food and mates. While some cell movement is random, directed movement stimulated by extracellular signals is our focus here. This involves a sequence of steps in which cells first detect extracellular chemical and/or mechanical signals via membrane receptors that activate signal transduction cascades and produce intracellular signals. These intracellular signals control the motile machinery of the cell and thereby determine the spatial localization of the sites of force generation needed to produce directed motion. Understanding how force generation within cells and mechanical interactions with their surroundings, including other cells, are controlled in space and time to produce cell-level movement is a major challenge, and involves many issues that are amenable to mathematical modelling.

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“…During chemotaxis, Gβγ subunits regulate actin assembly and migration, but the protein(s) linking Gβγ to the actin cytoskeleton remains unknown. The Gβγ effector, ElmoE in Dictyostelium, had demonstrated that it is required for GPCR-mediated chemotaxis [54]. As ElmoE associates with Gβγ and Dock-like proteins to activate the small GTPaseRac, in a GPCR-dependent manner, and also associates with Arp2/3 complex and F-actin, ElmoE serves as a link between chemoattractant GPCRs, G-proteins and the actin cytoskeleton.…”

Section: Anaphylatoxins Receptorsmentioning

confidence: 99%

“…As ElmoE associates with Gβγ and Dock-like proteins to activate the small GTPaseRac, in a GPCR-dependent manner, and also associates with Arp2/3 complex and F-actin, ElmoE serves as a link between chemoattractant GPCRs, G-proteins and the actin cytoskeleton. The pathway, consisting of GPCR, Gβγ, Elmo/Dock, Rac, and Arp2/3, spatially guides the growth of dendritic actin networks in pseudopods of eukaryotic cells during chemotaxis [54].…”

Section: Anaphylatoxins Receptorsmentioning

confidence: 99%

Anaphylatoxins: From Supposed Toxin Anaphylactics to Effective Mediators of the Early Events of Inflammation

Silva¹

2012

OJVM

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This review updates original data describing the experiments showing the complement origin of anaphylatoxins unexplainable submerged under the surface of the articles related to the subject. Next, recalls subsequent data describing the anaphylatoxins peptide nature and sequences, the cell receptors with which they interact and activate and the outcome of the cell responses. The review continues by highlighting the anaphylatoxin biological properties focusing on the unequivocal participation of these mediators in inflammation. The review concludes bringing data reinforcing the promising use of these peptides as molecular primers to create specific and efficient pharmacological antagonists.

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A Gβγ Effector, ElmoE, Transduces GPCR Signaling to the Actin Network during Chemotaxis

Cited by 72 publications

References 53 publications

Heterotrimeric G-protein shuttling via Gip1 extends the dynamic range of eukaryotic chemotaxis

Heterotrimeric G-protein shuttling via Gip1 extends the dynamic range of eukaryotic chemotaxis

Progress and perspectives in signal transduction, actin dynamics, and movement at the cell and tissue level: lessons fromDictyostelium

Anaphylatoxins: From Supposed Toxin Anaphylactics to Effective Mediators of the Early Events of Inflammation

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