Differentiation of Human T Cells Alters Their Repertoire of G Protein α-Subunits

Foley, John F.; Singh, Satya P.; Cantu, Michelle; Chen, Lingye; Zhang, Hongwei H.; Farber, Joshua M.

doi:10.1074/jbc.m110.128033

Cited by 15 publications

(12 citation statements)

References 82 publications

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“…In extreme cases, some G proteins might be present at negligible amounts, even if they couple with the highest efficiency to a particular GPCR. In addition, the repertoire of Gα subunits may also vary throughout development, which could contribute to changes in the nature of the responses to stimulation of a GPCR (74, 75). Third, a host of differentially abundant intracellular factors, such as RGS, AGS, and Ric8 proteins, can further shape GPCR fingerprints.…”

Section: Discussionmentioning

confidence: 99%

Distinct profiles of functional discrimination among G proteins determine the actions of G protein–coupled receptors

et al. 2015

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Members of the G protein coupled receptor (GPCR) family play key roles in many physiological functions and have been extensively exploited pharmacologically to treat diseases. Individual GPCRs exert diverse and distinct effects on cellular physiology and transduce signals by activating heterotrimeric G proteins. Mammalian genomes encode 16 different G protein alpha subunits, and each one of them has distinct properties. Here, we developed a single-platform, optical strategy for the direct monitoring of G protein activation in live cells, and using it we profiled the activities of individual GPCRs across a range of different G proteins, simultaneously quantifying both magnitude of their signaling and activation rates. We report that GPCRs engage multiple G proteins with varying efficacy and kinetics, generating fingerprint-like profiles that define individual receptors. We found that different classes of GPCR ligands, including full and partial agonists, allosteric modulators, and antagonists distinctly affected these fingerprints to functionally bias GPCR signaling. Finally, we showed that intracellular signaling modulators further altered the G protein–coupling profiles of GPCRs, which suggests that their differential expression may alter signaling outcomes in a cell-specific manner. . These observations suggest that the diversity of the effects of GPCRs on cellular physiology may be determined by their differential engagement of multiple G proteins with varying signal magnitudes and activation kinetics, properties that may be exploited pharmacologically.

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Section: Discussionmentioning

confidence: 99%

Distinct profiles of functional discrimination among G proteins determine the actions of G protein–coupled receptors

et al. 2015

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“…Furthermore, our results showed that three (miR‐20a‐5p, miR‐320a and miR‐324‐3p) of the eight plasma markers could be used for the early detection of HCC. As a target of miR‐320a/c/d in HCC cells, GNAI1 participates in numerous physiological processes, such as proliferation, adhesion and differentiation . GNAI1 , which is a member of the Gα inhibitory family, is significantly downregulated in HCC and can inhibit the invasion of HCC cells and play roles in the cyclin D1 pathway and regulation of proliferation .…”

Section: Discussionmentioning

confidence: 99%

Plasma miRNAs as early biomarkers for detecting hepatocellular carcinoma

Wen

Han

Chen

et al. 2015

Intl Journal of Cancer

200

129

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The early detection of hepatocellular carcinoma (HCC) presents a challenge because of the lack of specific biomarkers. Serum/ plasma microRNAs (miRNAs) can discriminate HCC patients from controls. We aimed to identify and evaluate HCC-associated plasma miRNAs originating from the liver as early biomarkers for detecting HCC. In this multicenter three-phase study, we first performed screening using both plasma (HCC before and after liver transplantation or liver hepatectomy) and tissue samples (HCC, para-carcinoma and cirrhotic tissues). Then, we evaluated the diagnostic potential of the miRNAs in two case-control studies (training and validation sets). Finally, we used two prospective cohorts to test the potential of the identified miRNAs for the early detection of HCC. During the screening phase, we identified ten miRNAs, eight of which (miR-20a-5p, miR-25-3p,

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“…More importantly, our findings suggest that the CXCR6 structure may have been optimized to perform in a range of cell types by maintaining promiscuous use of G i/o proteins. It is worth noting in this regard that we have shown that even within closely related leukocyte populations, such as subsets of human T cells, there are significant differences in the G i/o protein repertoire (Foley et al, 2010). Our current data show that subtle changes made in CXCR6 to match canonical sequences in the H3C can lead to cell-type specific deficiencies in the use of specific G i/o proteins, which can in turn compromise receptor function.…”

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confidence: 83%

“…In trying to understand the cell type-specific differences in the behaviors of the various mutants, we considered whether these could be due to differences in the mutants' abilities to couple to particular species of G proteins together with differences in the abundances of G protein species between the cell lines. To make direct quantitative comparisons among the different G protein a-subunit mRNAs by RT-PCR, we established that the corresponding sets of primers and probes showed equal efficiencies of amplification using plasmids containing each of the Ga cDNA sequences as substrates (Foley et al, 2010). We compared the levels of mRNAs for multiple Ga subunits in HEK-293T cells versus Jurkat E6-1 cells (Supplemental Fig.…”

Section: Roles For Noncanonical Sequences In Cxcr6mentioning

confidence: 99%

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Selectivity in the Use of G_i/oProteins Is Determined by the DRF Motif in CXCR6 and Is Cell-Type Specific

et al. 2015

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CXCR6, the receptor for CXCL16, is expressed on multiple cell types and can be a coreceptor for human immunodeficiency virus 1. Except for CXCR6, all human chemokine receptors contain the D 3.53 at positions 126-130. We investigated the importance and interdependence of the canonical D126 and the noncanonical F128 and V130 in CXCR6 by mutating D126 to Y, F128 to Y, and V130 to A singly and in combination. For comparison, we mutated the analogous positions D142, Y144, and A146 to Y, F, and V, respectively, in CCR6, a related receptor containing the canonical sequences. Mutants were analyzed in both human embryonic kidney 293T and Jurkat E6-1 cells. Our data show that for CXCR6 and/or CCR6, mutations in H3C can affect both receptor signaling and chemokine binding; noncanonical H3C sequences are functionally linked, with dual changes mitigating the effects of single mutations; mutations in H3C that compromise receptor activity show selective defects in the use of individual G i/o proteins; and the effects of mutations in H3C on receptor function and selectivity in G i/o protein use can be cell-type specific. Our findings indicate that the ability of CXCR6 to make promiscuous use of the available G i/o proteins is exquisitely dependent on sequences within the H3C and suggest that the native sequence allows for preservation of this function across different cellular environments.

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Differentiation of Human T Cells Alters Their Repertoire of G Protein α-Subunits

Cited by 15 publications

References 82 publications

Distinct profiles of functional discrimination among G proteins determine the actions of G protein–coupled receptors

Distinct profiles of functional discrimination among G proteins determine the actions of G protein–coupled receptors

Plasma miRNAs as early biomarkers for detecting hepatocellular carcinoma

Selectivity in the Use of G_i/oProteins Is Determined by the DRF Motif in CXCR6 and Is Cell-Type Specific

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Differentiation of Human T Cells Alters Their Repertoire of G Protein α-Subunits

Cited by 15 publications

References 82 publications

Distinct profiles of functional discrimination among G proteins determine the actions of G protein–coupled receptors

Distinct profiles of functional discrimination among G proteins determine the actions of G protein–coupled receptors

Plasma miRNAs as early biomarkers for detecting hepatocellular carcinoma

Selectivity in the Use of Gi/oProteins Is Determined by the DRF Motif in CXCR6 and Is Cell-Type Specific

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Selectivity in the Use of G_i/oProteins Is Determined by the DRF Motif in CXCR6 and Is Cell-Type Specific