A Chemical Biology Approach Demonstrates G Protein βγ Subunits Are Sufficient to Mediate Directional Neutrophil Chemotaxis

Surve, Chinmay R.; Lehmann, David M.; Smrcka, Alan V.

doi:10.1074/jbc.m114.576827

Cited by 43 publications

(34 citation statements)

References 35 publications

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“…Rather, the free βγ heterodimers are thought to differentially activate PLCβ2 and 3 on the one hand and PI3Kγ on the other (43). It is known that βγ subunits are sufficient to mediate directional neutrophil chemotaxis (44). The specificity of βγ subunits for downstream effectors is an emerging field for investigation (45, 46).…”

Section: Discussionmentioning

confidence: 99%

Gαi2 and Gαi3 Differentially Regulate Arrest from Flow and Chemotaxis in Mouse Neutrophils

Kuwano

Adler

Zhang

et al. 2016

The Journal of Immunology

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Leukocyte recruitment to inflammation sites progresses in a multistep cascade. Chemokines regulate multiple steps of the cascade including arrest, transmigration and chemotaxis. The most important chemokine receptor in mouse neutrophils is CXCR2, which couples through Gαi2 and Gαi3-containing heterotrimeric G proteins. Neutrophils arrest in response to CXCR2 stimulation. This is defective in Gαi2 deficient neutrophils. Here, we show that Gαi3 deficient neutrophils showed reduced transmigration but normal arrest in mice. We also tested Gαi2 or Gαi3 deficient neutrophils in a CXCL1 gradient generated by a microfluidic device. Gαi3, but not Gαi2, deficient neutrophils showed significantly reduced migration and directionality. This was confirmed in a model of sterile inflammation in vivo. Gαi2, but not Gαi3, deficient neutrophils showed decreased Ca2+ flux in response to CXCR2 stimulation. Conversely, Gαi3, but not Gαi2, deficient neutrophils exhibited reduced AKT phosphorylation upon CXCR2 stimulation. We conclude that Gαi2 controls arrest and Gαi3 controls transmigration and chemotaxis in response to chemokine stimulation of neutrophils.

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Section: Discussionmentioning

confidence: 99%

Gαi2 and Gαi3 Differentially Regulate Arrest from Flow and Chemotaxis in Mouse Neutrophils

Kuwano

Adler

Zhang

et al. 2016

The Journal of Immunology

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“…While chemotaxis depends upon the release of βγ subunits from Gα i (28,29), another measure of βγ signaling is to assess the activity of its downstream effectors. For example, freed βγ subunits activate phospholipase C-β2 leading to chemokine induced increases in intracellular calcium (30).…”

Section: Resultsmentioning

confidence: 99%

Normal Thymocyte Egress, T Cell Trafficking, and CD4+ T Cell Homeostasis Require Interactions between RGS Proteins and Gαi2

Hwang

Park

Harrison

et al. 2017

The Journal of Immunology

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Adaptive immunity depends upon mature thymocytes leaving the thymus to enter the bloodstream and the trafficking of T cells through lymphoid organs. Both of these requires heterotrimeric Gαi protein signaling, whose intensity and duration are controlled by RGS proteins. Here, we show that RGS protein/Gαi2 interactions are essential for normal thymocyte egress, T cell trafficking, and homeostasis. Mature thymocytes with a Gαi2 mutation that disables RGS protein binding accumulated in the perivascular channels of thymic corticomedullary venules. Severe reductions in peripheral naïve CD4+ T cells and Tregs occurred. The mutant CD4+ T cells adhered poorly to HEVs and exhibited defects in lymph node entrance and egress. The kinetics of chemokine receptor signaling were disturbed including chemokine induced integrin activation. Despite the thymic and lymph node egress defects, sphingosine-1-phosphate signaling was not obviously perturbed. This study reveals how RGS proteins modulate Gαi2 signaling to facilitate thymocyte egress and T cell trafficking.

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“…The immune system is certainly an area rich in signaling modulation and adaptation and requires dynamic signal processing and spatially integrated G-protein signaling (Cho and Kehrl, 2009;Kehrl et al, 2009). Indeed, G proteins and accessory proteins, such as regulator of G-protein signaling (RGS) proteins, play critical roles in signal processing in the immune system (Rudolph et al, 1995;Huang et al, 2003;Han et al, 2005Han et al, , 2006Skokowa et al, 2005;Hwang et al, 2007;Pero et al, 2007;Zarbock et al, 2007;Cho and Kehrl, 2009;Kehrl et al, 2009;Cho et al, 2012;Wiege et al, 2012Wiege et al, , 2013Surve et al, 2014Surve et al, , 2016; Rangel-Moreno et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Chemokine Signal Integration by Activator of G-Protein Signaling 4 (AGS4)

Robichaux

Branham‐O'Connor

Hwang

et al. 2017

J Pharmacol Exp Ther

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Activator of G-protein signaling 4 (AGS4)/G-protein signaling modulator 3 (Gpsm3) contains three G-protein regulatory (GPR) motifs, each of which can bind Gai-GDP free of Gbg. We previously demonstrated that the AGS4-Gai interaction is regulated by seven transmembrane-spanning receptors (7-TMR), which may reflect direct coupling of the GPR-Gai module to the receptor analogous to canonical Gabg heterotrimer. We have demonstrated that the AGS4-Gai complex is regulated by chemokine receptors in an agonist-dependent manner that is receptor-proximal. As an initial approach to investigate the functional role(s) of this regulated interaction in vivo, we analyzed leukocytes, in which AGS4/Gpsm3 is predominantly expressed, from AGS4/Gpsm3-null mice. Loss of AGS4/Gpsm3 resulted in mild but significant neutropenia and leukocytosis. Dendritic cells, T lymphocytes, and neutrophils from AGS4/Gpsm3-null mice also exhibited significant defects in chemoattractantdirected chemotaxis and extracellular signal-regulated kinase activation. An in vivo peritonitis model revealed a dramatic reduction in the ability of AGS4/Gpsm3-null neutrophils to migrate to primary sites of inflammation. Taken together, these data suggest that AGS4/Gpsm3 is required for proper chemokine signal processing in leukocytes and provide further evidence for the importance of the GPR-Gai module in the regulation of leukocyte function.

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A Chemical Biology Approach Demonstrates G Protein βγ Subunits Are Sufficient to Mediate Directional Neutrophil Chemotaxis

Cited by 43 publications

References 35 publications

Gαi2 and Gαi3 Differentially Regulate Arrest from Flow and Chemotaxis in Mouse Neutrophils

Gαi2 and Gαi3 Differentially Regulate Arrest from Flow and Chemotaxis in Mouse Neutrophils

Normal Thymocyte Egress, T Cell Trafficking, and CD4+ T Cell Homeostasis Require Interactions between RGS Proteins and Gαi2

Regulation of Chemokine Signal Integration by Activator of G-Protein Signaling 4 (AGS4)

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